Oligonucleotide Agonists Targeting Progranulin

ABSTRACT

The present invention relates to oligonucleotides which up-regulate or restore the expression of progranulin in cells, and their use in the treatment of neurological disorders, and disorders associated with progranulin haploinsufficiency.

REFERENCE TO SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted in ASCII format via EFS-Web and is hereby incorporated byreference in its entirety. Said ASCII copy, created on May 2, 2023, isnamed 067211.019US1.xml and is 4 MB in size.

FIELD OF INVENTION

The present invention relates to oligonucleotides which up-regulate orrestore the expression of progranulin in cells, and their use in thetreatment of neurological disorders, and disorders associated withprogranulin haploinsufficiency.

BACKGROUND

Progranulin (PGRN) is a highly conserved secreted protein that isexpressed in multiple cell types, both in the CNS and in peripheraltissues.

Deficiency of the secreted protein progranulin in the central nervoussystem causes the neurodegenerative disease fronto temporal dementia(FTD). Pathogenic progranulin (GRN) mutations lead to a loss of about50% in progranulin levels through haploinsufficiency and tointraneuronal aggregation of TDP-43 protein. Progranulin plays asupportive and protective role in numerous processes within the brain,including neurite outgrowth, synapse biology, response to exogenousstressors, lysosomal function, neuroinflammation, and angiogenesis inboth cell autonomous and non-autonomous manners.

In several neurodegenerative diseases TDP-43 is a common denominator.TDP-43 pathology is associated with cytoplasmic TDP-43 aggregation. Forexample, more than 95% of ALS patients display pathologicalmislocalization of TDP-43 and several mutations in its gene causefamilial ALS.

The presence of cytoplasmic TDP-43 aggregates is associated with aconcomitant loss of nuclear TDP-43, and there is evidence of both lossof function and gain of function associated pathophysiologies.

Both directly and via its conversion to granulins, progranulin regulateslysosomal function, cell growth, survival, repair, and inflammation.Progranulin has a major role in regulation of lysosomal functionassociated microglial responses in the CNS. Autosomal dominant mutationsof the progranulin (GRN) gene leading to protein haploinsufficiency arelinked to familial frontotemporal dementia with neuropathologicfrontotemporal lobar degeneration (FTLD) associated with accumulation ofTAR-DNA binding protein of 43kDA (TDP-43) inclusions (FTLD-TDP).Homozygous GRN mutations are linked to neuronal ceroid lipofuscinosis(NCL) (Townley, et al., Neurology. 2018 Jun. 12; 90(24): 1127).

Mutations in the progranulin gene (GRN) have recently been identified asa cause of about 5% of all FTD, including some sporadic cases. Recentstudies using mouse models has defined the expression of PGRN in thebrain (Petkau et al., 2010). PGRN is expressed late in neurodevelopment,localizing with markers of mature neurons. PGRN is expressed in neuronsin most brain regions, with highest expression in the thalamus,hippocampus, and cortex. Microglia cells also express progranulin, andthe level of expression is upregulated by microglial activation. Around70 different GRN mutations have been identified in FTD and all reduceprogranulin levels or result in loss of progranulin function.

WO 2020/077165 reports on AAV particle delivery of therapeutic nucleicacids, and lists progranulin as a potential gene of interest.

There is therefore an urgent need for therapeutic agents which canincrease the expression of progranulin.

SUMMARY OF INVENTION

The invention provides antisense oligonucleotide agonists of progranulinor antisense oligonucleotide progranulin agonists—i.e. antisenseoligonucleotides which are complementary to a progranulin nucleic acidsequence, and which are capable of up-regulating the expression ofprogranulin. Alternatively stated, the invention provides antisenseoligonucleotide positive modulators (i.e. agonists) of progranulin.

The antisense oligonucelotides of the invention may therefore be used torestore progranulin expression in cells which exhibit progranulinhaploinsufficiency, or to enhance expression of progranulin in cells.

The invention provides an antisense oligonucleotide progranulin agonist,wherein the antisense oligonucleotide is 8-40 nucleotides in length andcomprises a contiguous nucleotide sequence of 8-40 nucleotides in lengthwhich are complementary, such as fully complementary, to a humanprogranulin precursor-mRNA (pre-mRNA) or mature mRNA transcript.

The invention provides an antisense oligonucleotide progranulin agonist,wherein the antisense oligonucleotide is 12-40 nucleotides in length andcomprises a contiguous nucleotide sequence of 12-40 nucleotides inlength which are complementary, such as fully complementary, to a humanprogranulin precursor-mRNA (pre-mRNA) or mature mRNA transcript.

The invention provides an antisense oligonucleotide progranulin agonist,wherein the antisense oligonucleotide is 12-20 nucleotides in length andcomprises a contiguous nucleotide sequence of 12-20 nucleotides inlength which are complementary, such as fully complementary, to a humanprogranulin precursor-mRNA (pre-mRNA) or mature mRNA transcript.

The invention provides an antisense oligonucleotide progranulin agonist,wherein the antisense oligonucleotide is 14-18 nucleotides in length andcomprises a contiguous nucleotide sequence of 14-18 nucleotides inlength which are complementary, such as fully complementary, to a humanprogranulin precursor-mRNA (pre-mRNA) or mature mRNA transcript.

The invention provides an antisense oligonucleotide progranulin agonist,wherein the antisense oligonucleotide is 12-18 nucleotides in length andcomprises a contiguous nucleotide sequence of 12-18 nucleotides inlength which are complementary, such as fully complementary, to a humanprogranulin precursor-mRNA (pre-mRNA) or mature mRNA transcript.

The invention provides an antisense oligonucleotide progranulin agonist,wherein the antisense oligonucleotide is 8-40 nucleotides in length andcomprises a contiguous nucleotide sequence of 8-40 nucleotides in lengthwhich are complementary, such as fully complementary, to SEQ ID NO 2 or689.

The invention provides an antisense oligonucleotide progranulin agonist,wherein the antisense oligonucleotide is 12-40 nucleotides in length andcomprises a contiguous nucleotide sequence of 12-40 nucleotides inlength which are complementary, such as fully complementary, to SEQ IDNO 2 or 689.

The invention provides an antisense oligonucleotide progranulin agonist,wherein the antisense oligonucleotide is 12-20 nucleotides in length andcomprises a contiguous nucleotide sequence of 12-20 nucleotides inlength which are complementary, such as fully complementary, to SEQ IDNO 2 or 689.

The invention provides an antisense oligonucleotide progranulin agonist,wherein the antisense oligonucleotide is 14-18 nucleotides in length andcomprises a contiguous nucleotide sequence of 14-18 nucleotides inlength which are complementary, such as fully complementary, to SEQ IDNO 2 or 689.

The invention provides an antisense oligonucleotide progranulin agonist,wherein the antisense oligonucleotide is 12-18 nucleotides in length andcomprises a contiguous nucleotide sequence of 12-18 nucleotides inlength which are complementary, such as fully complementary, to SEQ IDNO 2 or 689.

The invention provides an antisense oligonucleotide progranulin agonist,wherein the antisense oligonucleotide is 8-40 nucleotides in length andcomprises a contiguous nucleotide sequence of 8-40 nucleotides in lengthwhich are complementary, such as fully complementary, to a sequenceselected from the group consisting of SEQ ID NO 683, 684, 685, 686, 687and 688.

The invention provides an antisense oligonucleotide progranulin agonist,wherein the antisense oligonucleotide is 12-40 nucleotides in length andcomprises a contiguous nucleotide sequence of 12-40 nucleotides inlength which are complementary, such as fully complementary, to asequence selected from the group consisting of SEQ ID NO 683, 684, 685,686, 687 and 688.

The invention provides an antisense oligonucleotide progranulin agonist,wherein the antisense oligonucleotide is 12-20 nucleotides in length andcomprises a contiguous nucleotide sequence of 12-20 nucleotides inlength which are complementary, such as fully complementary, to asequence selected from the group consisting of SEQ ID NO 683, 684, 685,686, 687 and 688.

The invention provides an antisense oligonucleotide progranulin agonist,wherein the antisense oligonucleotide is 14-18 nucleotides in length andcomprises a contiguous nucleotide sequence of 14-18 nucleotides inlength which are complementary, such as fully complementary, to a to asequence selected from the group consisting of SEQ ID NO 683, 684, 685,686, 687 and 688.

The invention provides an antisense oligonucleotide progranulin agonist,wherein the antisense oligonucleotide is 12-18 nucleotides in length andcomprises a contiguous nucleotide sequence of 12-18 nucleotides inlength which are complementary, such as fully complementary, to asequence selected from the group consisting of SEQ ID NO 683, 684, 685,686, 687 and 688.

The antisense oligonucleotide progranulin agonist may be 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 nucleotides in length. Insome embodiments the antisense oligonucleotide, or contiguous nucleotidesequence thereof, is 8-40, 12-40, 12-20, 14-18, 12-18 or 16-18nucleotides in length.

The contiguous nucleotide sequence may be 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,34, 35, 36, 37, 38, 39 or 40 nucleotides in length. In some embodiments,the contiguous nucleotide sequence is of a length of at least 12nucleotides in length, such as 12-16 or 12-18 nucleotides in length.

In some embodiments, the contiguous nucleotide sequence is the samelength as the antisense oligonucleotide progranulin agonist.

In some embodiments the antisense oligonucleotide consists of thecontiguous nucleotide sequence.

In some embodiments the antisense oligonucleotide is the contiguousnucleotide sequence.

In some embodiments, the contiguous nucleotide sequence is fullycomplementary to a sequence selected from the group consisting of SEQ IDNO 343-682.

In some embodiments the contiguous nucleotide sequence is complementary,such as fully complementary, to the human progranulin mature mRNA (SEQID NO: 1).

In some embodiments the contiguous nucleotide sequence is complementary,such as fully complementary, to the human progranulin precursor-mRNA(pre-mRNA) (SEQ ID NO: 3949).

In some embodiments, the contiguous nucleotide sequence iscomplementary, such as fully complementary, to a 5′UTR region of a humanprogranulin mature mRNA transcript. Herein the 5′ UTR is defined asnucleotides 38 to 241 according to RefSeq NM_002807.3 (SEQ ID NO 1).

In some embodiments, the contiguous nucleotide sequence iscomplementary, such as fully complementary, to nucleotides 38-246 of SEQID NO 1.

In some embodiments, the contiguous nucleotide sequence iscomplementary, such as fully complementary, to SEQ ID NO 689.

In some embodiments, the contiguous nucleotide sequence iscomplementary, such as fully complementary, to SEQ ID NO 2.

In some embodiments, the contiguous nucleotide sequence iscomplementary, such as fully complementary, to SEQ ID NO 683.

In some embodiments, the contiguous nucleotide sequence iscomplementary, such as fully complementary, to a sequence selected fromthe group consisting of SEQ ID NO 343-586.

In some embodiments, the contiguous nucleotide sequence iscomplementary, such as fully complementary, to a sequence selected fromthe group consisting of SEQ ID NO 568, SEQ ID NO 571, SEQ ID NO 575, SEQID NO 576, SEQ ID NO 577, SEQ ID NO 578, SEQ ID NO 584, & SEQ ID NO 586.

In some embodiments, the contiguous nucleotide sequence is a sequenceselected from the group consisting of SEQ ID NO 3-342, or at least 8contiguous nucleotides thereof.

In some embodiments, the contiguous nucleotide sequence is a sequenceselected from the group consisting of SEQ ID NO 3-342, or at least 9contiguous nucleotides thereof.

In some embodiments, the contiguous nucleotide sequence is a sequenceselected from the group consisting of SEQ ID NO 3-342, or at least 10contiguous nucleotides thereof.

In some embodiments, the contiguous nucleotide sequence is a sequenceselected from the group consisting of SEQ ID NO 3-342, or at least 11contiguous nucleotides thereof.

In some embodiments, the contiguous nucleotide sequence is a sequenceselected from the group consisting of SEQ ID NO 3-342, or at least 12contiguous nucleotides thereof.

In some embodiments, the contiguous nucleotide sequence is a sequenceselected from the group consisting of SEQ ID NO 3-342, or at least 13contiguous nucleotides thereof.

In some embodiments, the contiguous nucleotide sequence is a sequenceselected from the group consisting of SEQ ID NO 3-342, or at least 14contiguous nucleotides thereof.

In some embodiments, the contiguous nucleotide sequence is a sequenceselected from the group consisting of SEQ ID NO 3-342, or at least 15contiguous nucleotides thereof.

In some embodiments, the contiguous nucleotide sequence is a sequenceselected from the group consisting of SEQ ID NO 3-342, or at least 16contiguous nucleotides thereof.

In some embodiments, the contiguous nucleotide sequence is selected fromSEQ ID NO 105, SEQ ID NO 106, SEQ ID NO 110, SEQ ID NO 113, SEQ ID NO114, SEQ ID NO 231 and SEQ ID NO 241 or at least 8 or at least 10contiguous nucleotides thereof.

In some embodiments the contiguous nucleotide sequence is SEQ ID NO 106.

In some embodiments the contiguous nucleotide sequence is SEQ ID NO 110.

In some embodiments, the contiguous nucleotide sequence iscomplementary, such as fully complementary, to a 3′UTR region of a humanprogranulin mature mRNA transcript. Herein the 3′ UTR is defined asnucleotides 2044 to 2346 according to RefSeq NM_002807.3 (SEQ ID NO 1).

In some embodiments, the contiguous nucleotide sequence iscomplementary, such as fully complementary, to nucleotides 2039-2346 ofSEQ ID NO 1.

In some embodiments, the contiguous nucleotide sequence iscomplementary, such as fully complementary, to a sequence selected fromthe group consisting of SEQ ID NO 684, SEQ ID NO 685, SEQ ID NO 686, SEQID NO 687, and SEQ ID NO 688.

In some embodiments, the contiguous nucleotide sequence iscomplementary, such as fully complementary, to a sequence selected fromthe group consisting of SEQ ID NO 587-682.

In some embodiments, the contiguous nucleotide sequence iscomplementary, such as fully complementary, to a sequence selected fromthe group consisting of SEQ ID NO 607, SEQ ID NO 608, SEQ ID NO 609, SEQID NO 610, SEQ ID NO 611, SEQ ID NO 612, SEQ ID NO 619, SEQ ID NO 620,SEQ ID NO 633, SEQ ID NO 640, SEQ ID NO 641, SEQ ID NO 645, SEQ ID NO651, and SEQ ID NO 652.

In some embodiments, the contiguous nucleotide sequence iscomplementary, such as fully complementary, to a sequence selected fromthe group consisting of SEQ ID NO 2040-3386.

In some embodiments, the contiguous nucleotide sequence iscomplementary, such as fully complementary, to a sequence selected fromthe group consisting of SEQ ID NO 2040-3386 or at least 8 contiguousnucleotides thereof.

In some embodiments, the contiguous nucleotide sequence iscomplementary, such as fully complementary, to a sequence selected fromthe group consisting of SEQ ID NO 2040-3386 or at least 9 contiguousnucleotides thereof.

In some embodiments, the contiguous nucleotide sequence iscomplementary, such as fully complementary, to a sequence selected fromthe group consisting of SEQ ID NO 2040-3386 or at least 10 contiguousnucleotides thereof.

In some embodiments, the contiguous nucleotide sequence iscomplementary, such as fully complementary, to a sequence selected fromthe group consisting of SEQ ID NO 2040-3386 or at least 11 contiguousnucleotides thereof.

In some embodiments, the contiguous nucleotide sequence iscomplementary, such as fully complementary, to a sequence selected fromthe group consisting of SEQ ID NO 2040-3386 or at least 12 contiguousnucleotides thereof.

In some embodiments, the contiguous nucleotide sequence iscomplementary, such as fully complementary, to a sequence selected fromthe group consisting of SEQ ID NO 2040-3386 or at least 13 contiguousnucleotides thereof.

In some embodiments, the contiguous nucleotide sequence iscomplementary, such as fully complementary, to a sequence selected fromthe group consisting of SEQ ID NO 2040-3386 or at least 14 contiguousnucleotides thereof.

In some embodiments, the contiguous nucleotide sequence iscomplementary, such as fully complementary, to a sequence selected fromthe group consisting of SEQ ID NO 2040-3386 or at least 15 contiguousnucleotides thereof.

In some embodiments, the contiguous nucleotide sequence iscomplementary, such as fully complementary, to a sequence selected fromthe group consisting of SEQ ID NO 2040-3386 or at least 16 contiguousnucleotides thereof.

In some embodiments, the contiguous nucleotide sequence iscomplementary, such as fully complementary, to a sequence selected fromthe group consisting of SEQ ID 2321, SEQ ID 2322, SEQ ID 2324, SEQ ID2328, SEQ ID 2329, SEQ ID 2331, SEQ ID 2334, SEQ ID 2335, SEQ ID 2336,SEQ ID 2337, SEQ ID 2338, SEQ ID 2339, SEQ ID 2340, SEQ ID 2341, SEQ ID2342, SEQ ID 2345, SEQ ID 2346, SEQ ID 2347, SEQ ID 2348, SEQ ID 2349,SEQ ID 2350, SEQ ID 2351, SEQ ID 2352, SEQ ID 2353, SEQ ID 2354, SEQ ID2355, SEQ ID 2356, SEQ ID 2357, SEQ ID 2358, SEQ ID 2359, SEQ ID 2360,SEQ ID 2361, SEQ ID 2362, SEQ ID 2364, SEQ ID 2365, SEQ ID 2366, SEQ ID2367, SEQ ID 2368, SEQ ID 2369, SEQ ID 2370, SEQ ID 2371, SEQ ID 2372,SEQ ID 2373, SEQ ID 2374, SEQ ID 2375, SEQ ID 2376, SEQ ID 2377, SEQ ID2378, SEQ ID 2379, SEQ ID 2380, SEQ ID 2381, SEQ ID 2384, SEQ ID 2386,SEQ ID 2387, SEQ ID 2388, SEQ ID 2389, SEQ ID 2390, SEQ ID 2392, SEQ ID2393, SEQ ID 2394, SEQ ID 2395, SEQ ID 2396, SEQ ID 2397, SEQ ID 2398,SEQ ID 2399, SEQ ID 2400, SEQ ID 2401, SEQ ID 2403, SEQ ID 2404, SEQ ID2405, SEQ ID 2406, SEQ ID 2407, SEQ ID 2408, SEQ ID 2410, SEQ ID 2411,SEQ ID 2413, SEQ ID 2414, SEQ ID 2415, SEQ ID 2416, SEQ ID 2418, SEQ ID2419, SEQ ID 2421, SEQ ID 2424, SEQ ID 2425, SEQ ID 2426, SEQ ID 2427,SEQ ID 2428, SEQ ID 2429, SEQ ID 2430, SEQ ID 2431, SEQ ID 2432, SEQ ID2433, SEQ ID 2434, SEQ ID 2435, SEQ ID 2436, SEQ ID 2437, SEQ ID 2438,SEQ ID 2439, SEQ ID 2440, SEQ ID 2441, SEQ ID 2442, SEQ ID 2443, SEQ ID2444, SEQ ID 2445, SEQ ID 2446, SEQ ID 2447, SEQ ID 2448, SEQ ID 2449,SEQ ID 2450, SEQ ID 2451, SEQ ID 2452, SEQ ID 2453, SEQ ID 2454, SEQ ID2455, SEQ ID 2456, SEQ ID 2457, SEQ ID 2458, SEQ ID 2459, SEQ ID 2460,SEQ ID 2461, SEQ ID 2462, SEQ ID 2463, SEQ ID 2464, SEQ ID 2465, SEQ ID2466, SEQ ID 2467, SEQ ID 2468, SEQ ID 2469, SEQ ID 2470, SEQ ID 2471,SEQ ID 2472, SEQ ID 2473, SEQ ID 2474, SEQ ID 2475, SEQ ID 2476, SEQ ID2477, SEQ ID 2478, SEQ ID 2479, SEQ ID 2481, SEQ ID 2482, SEQ ID 2483,SEQ ID 2484, SEQ ID 2485, SEQ ID 2487, SEQ ID 2489, SEQ ID 2490, SEQ ID2491, SEQ ID 2492, SEQ ID 2493, SEQ ID 2494, SEQ ID 2495, SEQ ID 2496,SEQ ID 2497, SEQ ID 2498, SEQ ID 2499, SEQ ID 2501, SEQ ID 2502, SEQ ID2503, SEQ ID 2504, SEQ ID 2505, SEQ ID 2506, SEQ ID 2507, SEQ ID 2508,SEQ ID 2509, SEQ ID 2510, SEQ ID 2511, SEQ ID 2512, SEQ ID 2513, SEQ ID2514, SEQ ID 2515, SEQ ID 2516, SEQ ID 2518, SEQ ID 2519, SEQ ID 2520,SEQ ID 2521, SEQ ID 2522, SEQ ID 2523, SEQ ID 2524, SEQ ID 2525, SEQ ID2526, SEQ ID 2527, SEQ ID 2528, SEQ ID 2531, SEQ ID 2533, SEQ ID 2534,SEQ ID 2535, SEQ ID 2536, SEQ ID 2537, SEQ ID 2538, SEQ ID 2540, SEQ ID2541, SEQ ID 2542, SEQ ID 2544, SEQ ID 2546, SEQ ID 2547, SEQ ID 2549,SEQ ID 2550, SEQ ID 2551, SEQ ID 2553, SEQ ID 2554, SEQ ID 2555, SEQ ID2556, SEQ ID 2557, SEQ ID 2560, SEQ ID 2561, SEQ ID 2562, SEQ ID 2563,SEQ ID 2565, SEQ ID 2566, SEQ ID 2567, SEQ ID 2572, SEQ ID 2573, SEQ ID2574, SEQ ID 2575, SEQ ID 2576, SEQ ID 2577, SEQ ID 2578, SEQ ID 2579,SEQ ID 2580, SEQ ID 2581, SEQ ID 2582, SEQ ID 2583, SEQ ID 2584, SEQ ID2585, SEQ ID 2586, SEQ ID 2588, SEQ ID 2589, SEQ ID 2590, SEQ ID 2591,SEQ ID 2592, SEQ ID 2593, SEQ ID 2594, SEQ ID 2595, SEQ ID 2596, SEQ ID2597, SEQ ID 2598, SEQ ID 2599, SEQ ID 2601, SEQ ID 2602, SEQ ID 2603,SEQ ID 2604, SEQ ID 2606, SEQ ID 2610, SEQ ID 2613, SEQ ID 2614, SEQ ID2615, SEQ ID 2619, SEQ ID 2622, SEQ ID 2623, SEQ ID 2624, SEQ ID 2625,SEQ ID 2626, SEQ ID 2627, SEQ ID 2628, SEQ ID 2629, SEQ ID 2630, SEQ ID2631, SEQ ID 2632, SEQ ID 2633, SEQ ID 2634, SEQ ID 2635, SEQ ID 2636,SEQ ID 2637, SEQ ID 2638, SEQ ID 2639, SEQ ID 2640, SEQ ID 2641, SEQ ID2642, SEQ ID 2643, SEQ ID 2644, SEQ ID 2645, SEQ ID 2646, SEQ ID 2647,SEQ ID 2648, SEQ ID 2649, SEQ ID 2650, SEQ ID 2651, SEQ ID 2652, SEQ ID2653, SEQ ID 2654, SEQ ID 2655, SEQ ID 2656, SEQ ID 2658, SEQ ID 2659,SEQ ID 2660, SEQ ID 2661, SEQ ID 2662, SEQ ID 2663, SEQ ID 2664, SEQ ID2665, SEQ ID 2666, SEQ ID 2667, SEQ ID 2668, SEQ ID 2669, SEQ ID 2670,SEQ ID 2671, SEQ ID 2672, SEQ ID 2673, SEQ ID 2674, SEQ ID 2675, SEQ ID2676, SEQ ID 2677, SEQ ID 2678, SEQ ID 2679, SEQ ID 2680, SEQ ID 2681,SEQ ID 2682, SEQ ID 2683, SEQ ID 2684, SEQ ID 2685, SEQ ID 2686, SEQ ID2687, SEQ ID 2688, SEQ ID 2689, SEQ ID 2690, SEQ ID 2691, SEQ ID 2693,SEQ ID 2694, SEQ ID 2695, SEQ ID 2696, SEQ ID 2697, SEQ ID 2698, SEQ ID2699, SEQ ID 2700, SEQ ID 2701, SEQ ID 2702, SEQ ID 2703, SEQ ID 2704,SEQ ID 2705, SEQ ID 2706, SEQ ID 2707, SEQ ID 2708, SEQ ID 2709, SEQ ID2710, SEQ ID 2711, SEQ ID 2712, SEQ ID 2713, SEQ ID 2714, SEQ ID 2715,SEQ ID 2716, SEQ ID 2717, SEQ ID 2718, SEQ ID 2719, SEQ ID 2720, SEQ ID2721, SEQ ID 2722, SEQ ID 2723, SEQ ID 2726, SEQ ID 2727, SEQ ID 2728,SEQ ID 2729, SEQ ID 2730, SEQ ID 2733, SEQ ID 2734, SEQ ID 2735, SEQ ID2736, SEQ ID 2737, SEQ ID 2738, SEQ ID 2739, SEQ ID 2740, SEQ ID 2741,SEQ ID 2742, SEQ ID 2743, SEQ ID 2744, SEQ ID 2745, SEQ ID 2746, SEQ ID2747, SEQ ID 2748, SEQ ID 2749, SEQ ID 2750, SEQ ID 2751, SEQ ID 2752,SEQ ID 2753, SEQ ID 2754, SEQ ID 2755, SEQ ID 2756, SEQ ID 2757, SEQ ID2758, SEQ ID 2759, SEQ ID 2760, SEQ ID 2761, SEQ ID 2762, SEQ ID 2763,SEQ ID 2764, SEQ ID 2765, SEQ ID 2766, SEQ ID 2767, SEQ ID 2768, SEQ ID2769, SEQ ID 2770, SEQ ID 2771, SEQ ID 2772, SEQ ID 2773, SEQ ID 2774,SEQ ID 2775, SEQ ID 2815, SEQ ID 2816, SEQ ID 2817, SEQ ID 2818, SEQ ID2819, SEQ ID 2820, SEQ ID 2821, SEQ ID 2822, SEQ ID 2823, SEQ ID 2824,SEQ ID 2825, SEQ ID 2826, SEQ ID 2827, SEQ ID 2828, SEQ ID 2829, SEQ ID2830, SEQ ID 2831, SEQ ID 2832, SEQ ID 2833, SEQ ID 2834, SEQ ID 2835,SEQ ID 2836, SEQ ID 2837, SEQ ID 2838, SEQ ID 2839, SEQ ID 2840, SEQ ID2841, SEQ ID 2842, SEQ ID 2843, SEQ ID 2844, SEQ ID 2845, SEQ ID 2847,SEQ ID 2848, SEQ ID 2849, SEQ ID 2850, SEQ ID 2851, SEQ ID 2852, SEQ ID2853, SEQ ID 2854, SEQ ID 2855, SEQ ID 2858, SEQ ID 2859, SEQ ID 2860,SEQ ID 2861, SEQ ID 2862, SEQ ID 2863, SEQ ID 2864, SEQ ID 2865, SEQ ID2866, SEQ ID 2867, SEQ ID 2868, SEQ ID 2869, SEQ ID 2870, SEQ ID 2871,SEQ ID 2872, SEQ ID 2873, SEQ ID 2874, SEQ ID 2875, SEQ ID 2876, SEQ ID2878, SEQ ID 2879, SEQ ID 2880, SEQ ID 2881, SEQ ID 2882, SEQ ID 2883,SEQ ID 2884, SEQ ID 2885, SEQ ID 2886, SEQ ID 2887, SEQ ID 2888, SEQ ID2889, SEQ ID 2890, SEQ ID 2891, SEQ ID 2892, SEQ ID 2893, SEQ ID 2894,SEQ ID 2895, SEQ ID 2896, SEQ ID 2897, SEQ ID 2898, SEQ ID 2899, SEQ ID2900, SEQ ID 2901, SEQ ID 2902, SEQ ID 2903, SEQ ID 2904, SEQ ID 2905,SEQ ID 2906, SEQ ID 2907, SEQ ID 2908, SEQ ID 2909, SEQ ID 2910, SEQ ID2911, SEQ ID 2912, SEQ ID 2913, SEQ ID 2914, SEQ ID 2915, SEQ ID 2916,SEQ ID 2917, SEQ ID 2918, SEQ ID 2919, SEQ ID 2920, SEQ ID 2921, SEQ ID2922, SEQ ID 2923, SEQ ID 2924, SEQ ID 2925, SEQ ID 2926, SEQ ID 2927,SEQ ID 2928, SEQ ID 2929, SEQ ID 2930, SEQ ID 2931, SEQ ID 2932, SEQ ID2934, SEQ ID 2935, SEQ ID 2936, SEQ ID 2937, SEQ ID 2938, SEQ ID 2939,SEQ ID 2940, SEQ ID 2941, SEQ ID 2942, SEQ ID 2943, SEQ ID 2944, SEQ ID2945, SEQ ID 2946, SEQ ID 2947, SEQ ID 2948, SEQ ID 2949, SEQ ID 2950,SEQ ID 2951, SEQ ID 2953, SEQ ID 2954, SEQ ID 2955, SEQ ID 2956, SEQ ID2957, SEQ ID 2958, SEQ ID 2960, SEQ ID 2961, SEQ ID 2963, SEQ ID 2964,SEQ ID 2965, SEQ ID 2966, SEQ ID 2967, SEQ ID 2969, SEQ ID 2970, SEQ ID2971, SEQ ID 2972, SEQ ID 2973, SEQ ID 2974, SEQ ID 2975, SEQ ID 2976,SEQ ID 2977, SEQ ID 2978, SEQ ID 2979, SEQ ID 2980, SEQ ID 2981, SEQ ID2982, SEQ ID 2983, SEQ ID 2984, SEQ ID 2985, SEQ ID 3053, SEQ ID 3054,SEQ ID 3055, SEQ ID 3056, SEQ ID 3057, SEQ ID 3058, SEQ ID 3059, SEQ ID3060, SEQ ID 3061, SEQ ID 3062, SEQ ID 3063, SEQ ID 3064, SEQ ID 3065,SEQ ID 3066, SEQ ID 3068, SEQ ID 3069, SEQ ID 3070, SEQ ID 3071, SEQ ID3072, SEQ ID 3073, SEQ ID 3074, SEQ ID 3075, SEQ ID 3076, SEQ ID 3077,SEQ ID 3078, SEQ ID 3079, SEQ ID 3080, SEQ ID 3081, SEQ ID 3082, SEQ ID3083, SEQ ID 3084, SEQ ID 3085, SEQ ID 3086, SEQ ID 3087, SEQ ID 3088,SEQ ID 3089, SEQ ID 3090, SEQ ID 3091, SEQ ID 3092, SEQ ID 3093, SEQ ID3094, SEQ ID 3095, SEQ ID 3097, SEQ ID 3098, SEQ ID 3099, SEQ ID 3100,SEQ ID 3102, SEQ ID 3103, SEQ ID 3104, SEQ ID 3105, SEQ ID 3106, SEQ ID3107, SEQ ID 3108, SEQ ID 3109, SEQ ID 3110, SEQ ID 3112, SEQ ID 3113,SEQ ID 3115, SEQ ID 3116, SEQ ID 3117, SEQ ID 3119, SEQ ID 3120, SEQ ID3121, SEQ ID 3122, SEQ ID 3123, SEQ ID 3124, SEQ ID 3125, SEQ ID 3126,SEQ ID 3127, SEQ ID 3128, SEQ ID 3129, SEQ ID 3130, SEQ ID 3131, SEQ ID3132, SEQ ID 3133, SEQ ID 3134, SEQ ID 3135, SEQ ID 3136, SEQ ID 3137,SEQ ID 3138, SEQ ID 3139, SEQ ID 3140, SEQ ID 3141, SEQ ID 3142, SEQ ID3143, SEQ ID 3144, SEQ ID 3145, SEQ ID 3146, SEQ ID 3147, SEQ ID 3148,SEQ ID 3149, SEQ ID 3150, SEQ ID 3151, SEQ ID 3152, SEQ ID 3153, SEQ ID3154, SEQ ID 3155, SEQ ID 3156, SEQ ID 3157, SEQ ID 3158, SEQ ID 3159,SEQ ID 3160, SEQ ID 3161, SEQ ID 3162, SEQ ID 3163, SEQ ID 3164, SEQ ID3165, SEQ ID 3166, SEQ ID 3167, SEQ ID 3168, SEQ ID 3169, SEQ ID 3170,SEQ ID 3171, SEQ ID 3172, SEQ ID 3173, SEQ ID 3174, SEQ ID 3175, SEQ ID3176, SEQ ID 3177, SEQ ID 3178, SEQ ID 3179, SEQ ID 3180, SEQ ID 3181,SEQ ID 3182, SEQ ID 3183, SEQ ID 3184, SEQ ID 3185, SEQ ID 3186, SEQ ID3187, SEQ ID 3188, SEQ ID 3189, SEQ ID 3190, SEQ ID 3191, SEQ ID 3192,SEQ ID 3193, SEQ ID 3194, SEQ ID 3195, SEQ ID 3196, SEQ ID 3197, SEQ ID3198, SEQ ID 3199, SEQ ID 3200, SEQ ID 3201, SEQ ID 3202, SEQ ID 3203,SEQ ID 3204, SEQ ID 3205, SEQ ID 3206, SEQ ID 3207, SEQ ID 3208, SEQ ID3209, SEQ ID 3210, SEQ ID 3211, SEQ ID 3212, SEQ ID 3213, SEQ ID 3214,SEQ ID 3215, SEQ ID 3216, SEQ ID 3217, SEQ ID 3218, SEQ ID 3219, SEQ ID3220, SEQ ID 3221, SEQ ID 3222, SEQ ID 3223, SEQ ID 3224, SEQ ID 3225,SEQ ID 3226, SEQ ID 3227, SEQ ID 3228, SEQ ID 3229, SEQ ID 3230, SEQ ID3231, SEQ ID 3232, SEQ ID 3233, SEQ ID 3234, SEQ ID 3235, SEQ ID 3236,SEQ ID 3237, SEQ ID 3238, SEQ ID 3239, SEQ ID 3240, SEQ ID 3241, SEQ ID3242, SEQ ID 3243, SEQ ID 3244, SEQ ID 3245, SEQ ID 3246, SEQ ID 3248,SEQ ID 3249, SEQ ID 3250, SEQ ID 3251, SEQ ID 3252, SEQ ID 3253, SEQ ID3254, SEQ ID 3255, SEQ ID 3256, SEQ ID 3257, SEQ ID 3258, SEQ ID 3259,SEQ ID 3260, SEQ ID 3261, SEQ ID 3262, SEQ ID 3263, SEQ ID 3264, SEQ ID3265, SEQ ID 3266, SEQ ID 3267, SEQ ID 3268, SEQ ID 3269, SEQ ID 3270,SEQ ID 3271, SEQ ID 3272, SEQ ID 3273, SEQ ID 3275, SEQ ID 3276, SEQ ID3277, SEQ ID 3278, SEQ ID 3279, SEQ ID 3280, SEQ ID 3282, SEQ ID 3284,SEQ ID 3285, SEQ ID 3286, SEQ ID 3287, SEQ ID 3288, SEQ ID 3289, SEQ ID3291, SEQ ID 3292, SEQ ID 3293, SEQ ID 3294, SEQ ID 3295, SEQ ID 3296,SEQ ID 3297, SEQ ID 3298, SEQ ID 3299, SEQ ID 3300, SEQ ID 3301, SEQ ID3302, SEQ ID 3303, SEQ ID 3304, SEQ ID 3305, SEQ ID 3306, SEQ ID 3307,SEQ ID 3308, SEQ ID 3309, SEQ ID 3310, SEQ ID 3311, SEQ ID 3312, SEQ ID3313, SEQ ID 3314, SEQ ID 3315, SEQ ID 3316, SEQ ID 3317, SEQ ID 3318,SEQ ID 3320, SEQ ID 3321, SEQ ID 3322, SEQ ID 3323, SEQ ID 3324, SEQ ID3325, SEQ ID 3326, SEQ ID 3327, SEQ ID 3329, SEQ ID 3331, SEQ ID 3332,SEQ ID 3333, SEQ ID 3334, SEQ ID 3335, SEQ ID 3336, SEQ ID 3337, SEQ ID3338, SEQ ID 3339, SEQ ID 3340, SEQ ID 3342, SEQ ID 3343, SEQ ID 3344,SEQ ID 3345, SEQ ID 3346, SEQ ID 3347, SEQ ID 3348, SEQ ID 3349, SEQ ID3350, SEQ ID 3351, SEQ ID 3352, SEQ ID 3353, SEQ ID 3354, SEQ ID 3355,SEQ ID 3356, SEQ ID 3357, SEQ ID 3358, SEQ ID 3359, SEQ ID 3360, SEQ ID3361, SEQ ID 3362, SEQ ID 3363, SEQ ID 3364, SEQ ID 3365, SEQ ID 3366,SEQ ID 3367, SEQ ID 3368, SEQ ID 3369, SEQ ID 3370, SEQ ID 3371, SEQ ID3390, SEQ ID 3391, SEQ ID 3392, SEQ ID 3393, SEQ ID 3394, SEQ ID 3395,SEQ ID 3396, SEQ ID 3397, SEQ ID 3398, SEQ ID 3399, SEQ ID 3400, SEQ ID3401, SEQ ID 3402, SEQ ID 3403, SEQ ID 3404, SEQ ID 3405, SEQ ID 3406,SEQ ID 3407, SEQ ID 3408, SEQ ID 3409, SEQ ID 3410, SEQ ID 3411, SEQ ID3412, SEQ ID 3413, SEQ ID 3414, SEQ ID 3415, SEQ ID 3416, SEQ ID 3417,SEQ ID 3418, SEQ ID 3419, SEQ ID 3420, SEQ ID 3421, SEQ ID 3422, SEQ ID3423, SEQ ID 3424, SEQ ID 3425, SEQ ID 3426, SEQ ID 3427, SEQ ID 3428,SEQ ID 3429, SEQ ID 3430, SEQ ID 3431, SEQ ID 3432, SEQ ID 3433, SEQ ID3434, SEQ ID 3435, SEQ ID 3436, SEQ ID 3437, SEQ ID 3438, SEQ ID 3439,SEQ ID 3440, SEQ ID 3441, SEQ ID 3442, SEQ ID 3443, SEQ ID 3444, SEQ ID3445, SEQ ID 3446, SEQ ID 3447, SEQ ID 3448, SEQ ID 3449, SEQ ID 3450,SEQ ID 3451, SEQ ID 3452, SEQ ID 3453, SEQ ID 3454, SEQ ID 3460, SEQ ID3461, SEQ ID 3464, SEQ ID 3465, SEQ ID 3466, SEQ ID 3467, SEQ ID 3468,SEQ ID 3486, SEQ ID 3487, SEQ ID 3488, SEQ ID 3489, SEQ ID 3490, SEQ ID3491, SEQ ID 3493, SEQ ID 3494, SEQ ID 3496, SEQ ID 3497, SEQ ID 3501,SEQ ID 3505, SEQ ID 3508, SEQ ID 3511, SEQ ID 3512, SEQ ID 3516, SEQ ID3517, SEQ ID 3518, SEQ ID 3521, SEQ ID 3522, SEQ ID 3523, SEQ ID 3524,SEQ ID 3525, SEQ ID 3526, SEQ ID 3527, SEQ ID 3528, SEQ ID 3530, SEQ ID3531, SEQ ID 3532, SEQ ID 3534, SEQ ID 3535, SEQ ID 3536, SEQ ID 3538,SEQ ID 3539, SEQ ID 3541, SEQ ID 3542, SEQ ID 3543, SEQ ID 3544, SEQ ID3546, SEQ ID 3548, SEQ ID 3549, SEQ ID 3550, SEQ ID 3552, SEQ ID 3556,SEQ ID 3557, SEQ ID 3558, SEQ ID 3560, SEQ ID 3561, SEQ ID 3566, SEQ ID3567, SEQ ID 3568, SEQ ID 3569, SEQ ID 3571, SEQ ID 3572, SEQ ID 3573,SEQ ID 3574, SEQ ID 3576, SEQ ID 3577, SEQ ID 3578, SEQ ID 3580, SEQ ID3581, SEQ ID 3584, SEQ ID 3585, SEQ ID 3586, SEQ ID 3588, SEQ ID 3590,SEQ ID 3592, SEQ ID 3594, SEQ ID 3595, SEQ ID 3598, SEQ ID 3599, SEQ ID3600, SEQ ID 3601, SEQ ID 3602, SEQ ID 3603, SEQ ID 3605, SEQ ID 3607,SEQ ID 3609, SEQ ID 3610, SEQ ID 3613, SEQ ID 3614, SEQ ID 3615, SEQ ID3616, SEQ ID 3617, SEQ ID 3621, SEQ ID 3623, SEQ ID 3624, SEQ ID 3625,SEQ ID 3626, SEQ ID 3627, SEQ ID 3628, SEQ ID 3629, SEQ ID 3630, SEQ ID3631, SEQ ID 3632, SEQ ID 3633, SEQ ID 3636, SEQ ID 3637, SEQ ID 3638,SEQ ID 3639, SEQ ID 3641, SEQ ID 3642, SEQ ID 3643, SEQ ID 3645, SEQ ID3647, SEQ ID 3648, SEQ ID 3649, SEQ ID 3651, SEQ ID 3654, SEQ ID 3656,SEQ ID 3659, SEQ ID 3660, SEQ ID 3661, SEQ ID 3663, SEQ ID 3664, SEQ ID3665, SEQ ID 3666, SEQ ID 3670, SEQ ID 3672, SEQ ID 3676, SEQ ID 3678,SEQ ID 3679, SEQ ID 3680, SEQ ID 3681, SEQ ID 3682, SEQ ID 3683, SEQ ID3684, SEQ ID 3685, SEQ ID 3686, SEQ ID 3687, SEQ ID 3688, SEQ ID 3689,SEQ ID 3690, SEQ ID 3691, SEQ ID 3692, SEQ ID 3693, SEQ ID 3694, SEQ ID3695, SEQ ID 3696, SEQ ID 3697, SEQ ID 3698, SEQ ID 3699, SEQ ID 3700,SEQ ID 3701, SEQ ID 3702, SEQ ID 3703, SEQ ID 3704, SEQ ID 3705, SEQ ID3706, SEQ ID 3707, SEQ ID 3708, SEQ ID 3709, SEQ ID 3710, SEQ ID 3711,SEQ ID 3712, SEQ ID 3713, SEQ ID 3714, SEQ ID 3715, SEQ ID 3716, SEQ ID3717, SEQ ID 3718, SEQ ID 3719, SEQ ID 3720, SEQ ID 3721, SEQ ID 3722,SEQ ID 3723, SEQ ID 3724, SEQ ID 3725, SEQ ID 3726, SEQ ID 3727, SEQ ID3729, SEQ ID 3730, SEQ ID 3731, SEQ ID 3732, SEQ ID 3733, SEQ ID 3734,SEQ ID 3735, SEQ ID 3736, SEQ ID 3737, SEQ ID 3738, SEQ ID 3739, SEQ ID3740, SEQ ID 3741, SEQ ID 3742, SEQ ID 3743, SEQ ID 3744, SEQ ID 3745,SEQ ID 3746, SEQ ID 3747, SEQ ID 3748, SEQ ID 3749, SEQ ID 3750, SEQ ID3751, SEQ ID 3752, SEQ ID 3753, SEQ ID 3754, SEQ ID 3755, SEQ ID 3774,SEQ ID 3775, SEQ ID 3776, SEQ ID 3777, SEQ ID 3778, SEQ ID 3779, SEQ ID3780, SEQ ID 3781, SEQ ID 3782, SEQ ID 3783, SEQ ID 3784, SEQ ID 3785,SEQ ID 3786, SEQ ID 3787, SEQ ID 3788, SEQ ID 3789, SEQ ID 3790, SEQ ID3791, SEQ ID 3792, SEQ ID 3793, SEQ ID 3794, SEQ ID 3795, SEQ ID 3796,SEQ ID 3797, SEQ ID 3798, SEQ ID 3799, SEQ ID 3800, SEQ ID 3801, SEQ ID3802, SEQ ID 3803, SEQ ID 3804, SEQ ID 3805, SEQ ID 3806, SEQ ID 3807,SEQ ID 3808, SEQ ID 3809, SEQ ID 3810, SEQ ID 3811, SEQ ID 3812, SEQ ID3813, SEQ ID 3814, SEQ ID 3815, SEQ ID 3816, SEQ ID 3817, SEQ ID 3818,SEQ ID 3819, SEQ ID 3820, SEQ ID 3821, SEQ ID 3822, SEQ ID 3823, SEQ ID3824, SEQ ID 3825, SEQ ID 3826, SEQ ID 3827, SEQ ID 3828, SEQ ID 3829,SEQ ID 3830, SEQ ID 3831, SEQ ID 3832, SEQ ID 3833, SEQ ID 3834, SEQ ID3835, SEQ ID 3836, SEQ ID 3837, SEQ ID 3838, SEQ ID 3839, SEQ ID 3840,SEQ ID 3841, SEQ ID 3842, SEQ ID 3844, SEQ ID 3848, SEQ ID 3850, SEQ ID3851, SEQ ID 3852, SEQ ID 3853, SEQ ID 3867, SEQ ID 3868, SEQ ID 3869,SEQ ID 3870, SEQ ID 3871, SEQ ID 3872, SEQ ID 3873, SEQ ID 3874, SEQ ID3875, SEQ ID 3876, SEQ ID 3877, SEQ ID 3878, SEQ ID 3879, SEQ ID 3880,SEQ ID 3881, SEQ ID 3882, SEQ ID 3883, SEQ ID 3884, SEQ ID 3885, SEQ ID3886, SEQ ID 3887, SEQ ID 3888, SEQ ID 3889, SEQ ID 3890, SEQ ID 3891,SEQ ID 3892, SEQ ID 3893, SEQ ID 3894, SEQ ID 3895, SEQ ID 3896, SEQ ID3897, SEQ ID 3898, SEQ ID 3899, SEQ ID 3900, SEQ ID 3901, SEQ ID 3902,SEQ ID 3903, SEQ ID 3904, SEQ ID 3905, SEQ ID 3906, SEQ ID 3907, SEQ ID3908, SEQ ID 3909, SEQ ID 3910, SEQ ID 3911, SEQ ID 3912, SEQ ID 3913,SEQ ID 3914, SEQ ID 3915, SEQ ID 3916, SEQ ID 3917, SEQ ID 3918, SEQ ID3919, SEQ ID 3920, SEQ ID 3921, SEQ ID 3922, SEQ ID 3923, SEQ ID 3924,SEQ ID 3925, SEQ ID 3926, SEQ ID 3927, SEQ ID 3928, SEQ ID 3929, SEQ ID3930, SEQ ID 3931, SEQ ID 3932, SEQ ID 3933, SEQ ID 3934, SEQ ID 3935,SEQ ID 3936, SEQ ID 3937, SEQ ID 3938, SEQ ID 3939, SEQ ID 3940, SEQ ID3941, SEQ ID 3942, SEQ ID 3943, SEQ ID 3944, SEQ ID 3945, SEQ ID 3946,SEQ ID 3947, and SEQ ID 3948, or at least 8, 9, 10, 11, 12, 13, 14, 15or 16 contiguous nucleotides thereof.

In some embodiments, the contiguous nucleotide sequence iscomplementary, such as fully complementary, to a sequence selected fromthe group consisting of SEQ ID 2321, SEQ ID 2335, SEQ ID 2336, SEQ ID2337, SEQ ID 2338, SEQ ID 2339, SEQ ID 2348, SEQ ID 2349, SEQ ID 2351,SEQ ID 2352, SEQ ID 2353, SEQ ID 2354, SEQ ID 2355, SEQ ID 2358, SEQ ID2360, SEQ ID 2364, SEQ ID 2365, SEQ ID 2366, SEQ ID 2367, SEQ ID 2369,SEQ ID 2371, SEQ ID 2373, SEQ ID 2375, SEQ ID 2386, SEQ ID 2387, SEQ ID2388, SEQ ID 2389, SEQ ID 2394, SEQ ID 2403, SEQ ID 2426, SEQ ID 2428,SEQ ID 2429, SEQ ID 2430, SEQ ID 2431, SEQ ID 2432, SEQ ID 2435, SEQ ID2440, SEQ ID 2441, SEQ ID 2442, SEQ ID 2444, SEQ ID 2446, SEQ ID 2447,SEQ ID 2450, SEQ ID 2451, SEQ ID 2452, SEQ ID 2453, SEQ ID 2454, SEQ ID2455, SEQ ID 2456, SEQ ID 2458, SEQ ID 2459, SEQ ID 2461, SEQ ID 2463,SEQ ID 2464, SEQ ID 2465, SEQ ID 2466, SEQ ID 2467, SEQ ID 2468, SEQ ID2469, SEQ ID 2470, SEQ ID 2471, SEQ ID 2472, SEQ ID 2473, SEQ ID 2474,SEQ ID 2475, SEQ ID 2476, SEQ ID 2477, SEQ ID 2478, SEQ ID 2482, SEQ ID2483, SEQ ID 2484, SEQ ID 2485, SEQ ID 2487, SEQ ID 2489, SEQ ID 2494,SEQ ID 2495, SEQ ID 2496, SEQ ID 2497, SEQ ID 2499, SEQ ID 2501, SEQ ID2502, SEQ ID 2504, SEQ ID 2506, SEQ ID 2507, SEQ ID 2508, SEQ ID 2509,SEQ ID 2511, SEQ ID 2513, SEQ ID 2515, SEQ ID 2516, SEQ ID 2518, SEQ ID2519, SEQ ID 2520, SEQ ID 2521, SEQ ID 2523, SEQ ID 2525, SEQ ID 2534,SEQ ID 2537, SEQ ID 2544, SEQ ID 2546, SEQ ID 2554, SEQ ID 2555, SEQ ID2556, SEQ ID 2560, SEQ ID 2561, SEQ ID 2562, SEQ ID 2595, SEQ ID 2626,SEQ ID 2628, SEQ ID 2629, SEQ ID 2630, SEQ ID 2631, SEQ ID 2633, SEQ ID2638, SEQ ID 2639, SEQ ID 2640, SEQ ID 2649, SEQ ID 2651, SEQ ID 2652,SEQ ID 2655, SEQ ID 2658, SEQ ID 2665, SEQ ID 2666, SEQ ID 2667, SEQ ID2669, SEQ ID 2670, SEQ ID 2676, SEQ ID 2677, SEQ ID 2678, SEQ ID 2679,SEQ ID 2682, SEQ ID 2686, SEQ ID 2688, SEQ ID 2689, SEQ ID 2691, SEQ ID2694, SEQ ID 2698, SEQ ID 2699, SEQ ID 2700, SEQ ID 2701, SEQ ID 2703,SEQ ID 2706, SEQ ID 2709, SEQ ID 2711, SEQ ID 2712, SEQ ID 2713, SEQ ID2714, SEQ ID 2719, SEQ ID 2720, SEQ ID 2721, SEQ ID 2737, SEQ ID 2739,SEQ ID 2740, SEQ ID 2741, SEQ ID 2742, SEQ ID 2743, SEQ ID 2744, SEQ ID2745, SEQ ID 2746, SEQ ID 2747, SEQ ID 2748, SEQ ID 2749, SEQ ID 2750,SEQ ID 2751, SEQ ID 2752, SEQ ID 2753, SEQ ID 2754, SEQ ID 2755, SEQ ID2756, SEQ ID 2757, SEQ ID 2758, SEQ ID 2760, SEQ ID 2763, SEQ ID 2764,SEQ ID 2765, SEQ ID 2766, SEQ ID 2767, SEQ ID 2768, SEQ ID 2769, SEQ ID2770, SEQ ID 2771, SEQ ID 2772, SEQ ID 2774, SEQ ID 2816, SEQ ID 2817,SEQ ID 2818, SEQ ID 2819, SEQ ID 2820, SEQ ID 2824, SEQ ID 2828, SEQ ID2829, SEQ ID 2830, SEQ ID 2831, SEQ ID 2832, SEQ ID 2833, SEQ ID 2834,SEQ ID 2835, SEQ ID 2836, SEQ ID 2837, SEQ ID 2851, SEQ ID 2852, SEQ ID2866, SEQ ID 2871, SEQ ID 2872, SEQ ID 2886, SEQ ID 2887, SEQ ID 2890,SEQ ID 2891, SEQ ID 2892, SEQ ID 2895, SEQ ID 2896, SEQ ID 2899, SEQ ID2904, SEQ ID 2910, SEQ ID 2911, SEQ ID 2912, SEQ ID 2913, SEQ ID 2914,SEQ ID 2916, SEQ ID 2918, SEQ ID 2919, SEQ ID 2920, SEQ ID 2922, SEQ ID2925, SEQ ID 2926, SEQ ID 2932, SEQ ID 2939, SEQ ID 2941, SEQ ID 2942,SEQ ID 2943, SEQ ID 2972, SEQ ID 2973, SEQ ID 2974, SEQ ID 2975, SEQ ID2976, SEQ ID 2977, SEQ ID 2980, SEQ ID 2983, SEQ ID 2985, SEQ ID 3053,SEQ ID 3054, SEQ ID 3055, SEQ ID 3056, SEQ ID 3058, SEQ ID 3059, SEQ ID3060, SEQ ID 3061, SEQ ID 3062, SEQ ID 3063, SEQ ID 3064, SEQ ID 3065,SEQ ID 3066, SEQ ID 3068, SEQ ID 3069, SEQ ID 3070, SEQ ID 3071, SEQ ID3072, SEQ ID 3073, SEQ ID 3074, SEQ ID 3075, SEQ ID 3076, SEQ ID 3077,SEQ ID 3078, SEQ ID 3079, SEQ ID 3082, SEQ ID 3083, SEQ ID 3084, SEQ ID3085, SEQ ID 3088, SEQ ID 3089, SEQ ID 3090, SEQ ID 3091, SEQ ID 3092,SEQ ID 3095, SEQ ID 3097, SEQ ID 3102, SEQ ID 3106, SEQ ID 3108, SEQ ID3110, SEQ ID 3116, SEQ ID 3120, SEQ ID 3121, SEQ ID 3125, SEQ ID 3126,SEQ ID 3133, SEQ ID 3134, SEQ ID 3135, SEQ ID 3137, SEQ ID 3138, SEQ ID3140, SEQ ID 3141, SEQ ID 3142, SEQ ID 3143, SEQ ID 3145, SEQ ID 3148,SEQ ID 3152, SEQ ID 3153, SEQ ID 3156, SEQ ID 3157, SEQ ID 3158, SEQ ID3159, SEQ ID 3160, SEQ ID 3161, SEQ ID 3162, SEQ ID 3163, SEQ ID 3164,SEQ ID 3165, SEQ ID 3166, SEQ ID 3167, SEQ ID 3168, SEQ ID 3169, SEQ ID3170, SEQ ID 3172, SEQ ID 3173, SEQ ID 3174, SEQ ID 3175, SEQ ID 3176,SEQ ID 3177, SEQ ID 3178, SEQ ID 3179, SEQ ID 3180, SEQ ID 3181, SEQ ID3182, SEQ ID 3183, SEQ ID 3184, SEQ ID 3186, SEQ ID 3188, SEQ ID 3191,SEQ ID 3193, SEQ ID 3196, SEQ ID 3197, SEQ ID 3203, SEQ ID 3205, SEQ ID3206, SEQ ID 3207, SEQ ID 3210, SEQ ID 3211, SEQ ID 3212, SEQ ID 3213,SEQ ID 3214, SEQ ID 3215, SEQ ID 3216, SEQ ID 3217, SEQ ID 3218, SEQ ID3219, SEQ ID 3221, SEQ ID 3222, SEQ ID 3223, SEQ ID 3224, SEQ ID 3227,SEQ ID 3236, SEQ ID 3237, SEQ ID 3238, SEQ ID 3239, SEQ ID 3240, SEQ ID3241, SEQ ID 3242, SEQ ID 3243, SEQ ID 3244, SEQ ID 3245, SEQ ID 3246,SEQ ID 3248, SEQ ID 3249, SEQ ID 3250, SEQ ID 3251, SEQ ID 3252, SEQ ID3254, SEQ ID 3258, SEQ ID 3259, SEQ ID 3261, SEQ ID 3263, SEQ ID 3265,SEQ ID 3266, SEQ ID 3267, SEQ ID 3271, SEQ ID 3272, SEQ ID 3273, SEQ ID3276, SEQ ID 3277, SEQ ID 3279, SEQ ID 3286, SEQ ID 3295, SEQ ID 3297,SEQ ID 3305, SEQ ID 3307, SEQ ID 3309, SEQ ID 3312, SEQ ID 3313, SEQ ID3314, SEQ ID 3316, SEQ ID 3317, SEQ ID 3318, SEQ ID 3320, SEQ ID 3332,SEQ ID 3335, SEQ ID 3336, SEQ ID 3337, SEQ ID 3338, SEQ ID 3339, SEQ ID3340, SEQ ID 3342, SEQ ID 3343, SEQ ID 3345, SEQ ID 3346, SEQ ID 3347,SEQ ID 3348, SEQ ID 3349, SEQ ID 3350, SEQ ID 3351, SEQ ID 3352, SEQ ID3353, SEQ ID 3354, SEQ ID 3355, SEQ ID 3356, SEQ ID 3359, SEQ ID 3360,SEQ ID 3361, SEQ ID 3362, SEQ ID 3363, SEQ ID 3364, SEQ ID 3365, SEQ ID3366, SEQ ID 3369, SEQ ID 3370, SEQ ID 3390, SEQ ID 3392, SEQ ID 3393,SEQ ID 3394, SEQ ID 3395, SEQ ID 3396, SEQ ID 3397, SEQ ID 3398, SEQ ID3399, SEQ ID 3401, SEQ ID 3403, SEQ ID 3404, SEQ ID 3407, SEQ ID 3408,SEQ ID 3409, SEQ ID 3410, SEQ ID 3411, SEQ ID 3412, SEQ ID 3413, SEQ ID3414, SEQ ID 3415, SEQ ID 3417, SEQ ID 3419, SEQ ID 3420, SEQ ID 3422,SEQ ID 3423, SEQ ID 3424, SEQ ID 3428, SEQ ID 3429, SEQ ID 3430, SEQ ID3432, SEQ ID 3433, SEQ ID 3434, SEQ ID 3435, SEQ ID 3436, SEQ ID 3437,SEQ ID 3439, SEQ ID 3440, SEQ ID 3441, SEQ ID 3442, SEQ ID 3443, SEQ ID3444, SEQ ID 3445, SEQ ID 3446, SEQ ID 3447, SEQ ID 3448, SEQ ID 3449,SEQ ID 3450, SEQ ID 3451, SEQ ID 3452, SEQ ID 3460, SEQ ID 3461, SEQ ID3466, SEQ ID 3467, SEQ ID 3468, SEQ ID 3490, SEQ ID 3494, SEQ ID 3496,SEQ ID 3501, SEQ ID 3505, SEQ ID 3511, SEQ ID 3512, SEQ ID 3516, SEQ ID3517, SEQ ID 3521, SEQ ID 3522, SEQ ID 3556, SEQ ID 3557, SEQ ID 3561,SEQ ID 3566, SEQ ID 3567, SEQ ID 3568, SEQ ID 3569, SEQ ID 3571, SEQ ID3572, SEQ ID 3576, SEQ ID 3578, SEQ ID 3580, SEQ ID 3584, SEQ ID 3594,SEQ ID 3613, SEQ ID 3614, SEQ ID 3624, SEQ ID 3625, SEQ ID 3626, SEQ ID3627, SEQ ID 3628, SEQ ID 3633, SEQ ID 3641, SEQ ID 3643, SEQ ID 3648,SEQ ID 3651, SEQ ID 3654, SEQ ID 3656, SEQ ID 3659, SEQ ID 3660, SEQ ID3661, SEQ ID 3670, SEQ ID 3676, SEQ ID 3680, SEQ ID 3681, SEQ ID 3683,SEQ ID 3684, SEQ ID 3685, SEQ ID 3686, SEQ ID 3687, SEQ ID 3688, SEQ ID3689, SEQ ID 3691, SEQ ID 3693, SEQ ID 3694, SEQ ID 3695, SEQ ID 3696,SEQ ID 3698, SEQ ID 3700, SEQ ID 3701, SEQ ID 3703, SEQ ID 3704, SEQ ID3707, SEQ ID 3708, SEQ ID 3709, SEQ ID 3710, SEQ ID 3711, SEQ ID 3712,SEQ ID 3713, SEQ ID 3714, SEQ ID 3715, SEQ ID 3716, SEQ ID 3717, SEQ ID3718, SEQ ID 3719, SEQ ID 3720, SEQ ID 3721, SEQ ID 3722, SEQ ID 3723,SEQ ID 3725, SEQ ID 3744, SEQ ID 3747, SEQ ID 3748, SEQ ID 3749, SEQ ID3750, SEQ ID 3751, SEQ ID 3752, SEQ ID 3753, SEQ ID 3754, SEQ ID 3755,SEQ ID 3774, SEQ ID 3775, SEQ ID 3776, SEQ ID 3786, SEQ ID 3788, SEQ ID3790, SEQ ID 3791, SEQ ID 3793, SEQ ID 3794, SEQ ID 3795, SEQ ID 3796,SEQ ID 3797, SEQ ID 3798, SEQ ID 3799, SEQ ID 3800, SEQ ID 3801, SEQ ID3802, SEQ ID 3803, SEQ ID 3804, SEQ ID 3805, SEQ ID 3809, SEQ ID 3810,SEQ ID 3811, SEQ ID 3812, SEQ ID 3813, SEQ ID 3814, SEQ ID 3815, SEQ ID3821, SEQ ID 3822, SEQ ID 3823, SEQ ID 3824, SEQ ID 3825, SEQ ID 3826,SEQ ID 3827, SEQ ID 3828, SEQ ID 3830, SEQ ID 3831, SEQ ID 3832, SEQ ID3834, SEQ ID 3836, SEQ ID 3837, SEQ ID 3838, SEQ ID 3839, SEQ ID 3840,SEQ ID 3841, SEQ ID 3842, SEQ ID 3844, SEQ ID 3850, SEQ ID 3852, SEQ ID3867, SEQ ID 3868, SEQ ID 3870, SEQ ID 3871, SEQ ID 3872, SEQ ID 3873,SEQ ID 3874, SEQ ID 3875, SEQ ID 3876, SEQ ID 3879, SEQ ID 3880, SEQ ID3881, SEQ ID 3882, SEQ ID 3883, SEQ ID 3884, SEQ ID 3885, SEQ ID 3886,SEQ ID 3887, SEQ ID 3888, SEQ ID 3889, SEQ ID 3890, SEQ ID 3891, SEQ ID3892, SEQ ID 3893, SEQ ID 3894, SEQ ID 3895, SEQ ID 3896, SEQ ID 3897,SEQ ID 3908, SEQ ID 3909, SEQ ID 3910, SEQ ID 3911, SEQ ID 3912, SEQ ID3913, SEQ ID 3922, SEQ ID 3923, SEQ ID 3930, SEQ ID 3935, SEQ ID 3936,SEQ ID 3937, SEQ ID 3938, SEQ ID 3939, SEQ ID 3940, SEQ ID 3944, SEQ ID3945, SEQ ID 3946, SEQ ID 3947, and SEQ ID 3948, or at least 8, 9, 10,11, 12, 13, 14, 15 or 16 contiguous nucleotides thereof.

In some embodiments the contiguous nucleotide sequence is complementary,such as fully complementary, to at least 8 contiguous nucleotides of anyof the target sequences recited herein.

In some embodiments the contiguous nucleotide sequence is complementary,such as fully complementary, to at least 9 contiguous nucleotides of anyof the target sequences recited herein.

In some embodiments the contiguous nucleotide sequence is complementary,such as fully complementary, to at least 10 contiguous nucleotidescontiguous nucleotides of any of the target sequences recited herein.

In some embodiments the contiguous nucleotide sequence is complementary,such as fully complementary, to at least 11 contiguous nucleotidescontiguous nucleotides of any of the target sequences recited herein.

In some embodiments the contiguous nucleotide sequence is complementary,such as fully complementary, to at least 12 contiguous nucleotidescontiguous nucleotides of any of the target sequences recited herein.

In some embodiments the contiguous nucleotide sequence is complementary,such as fully complementary, to at least 13 contiguous nucleotidescontiguous nucleotides of any of the target sequences recited herein.

In some embodiments the contiguous nucleotide sequence is complementary,such as fully complementary, to at least 14 contiguous nucleotidescontiguous nucleotides of any of the target sequences recited herein.

In some embodiments the contiguous nucleotide sequence is complementary,such as fully complementary, to at least 15 contiguous nucleotidescontiguous nucleotides of any of the target sequences recited herein.

In some embodiments the contiguous nucleotide sequence is complementary,such as fully complementary, to at least 16 contiguous nucleotidescontiguous nucleotides of any of the target sequences recited herein.

In some embodiments, the antisense oligonucleotide progranulin agonistis or comprises an antisense oligonucleotide mixmer or totalmer. In someembodiments, the contiguous nucleotide sequence is a mixmer or atolalmer.

In some embodiments, the antisense oligonucleotide progranulin agonistor contiguous nucleotide sequence thereof is 10-20 nucleotides inlength.

In some embodiments, the antisense oligonucleotide progranulin agonistis selected from the group consisting of SEQ ID NOs 3-342.

In some embodiments, the antisense oligonucleotide progranulin agonistis selected from the group consisting of SEQ ID NOs 693-2039.

In some embodiments, the antisense oligonucleotide progranulin agonistis selected from the group consisting of SEQ ID 693, SEQ ID 694, SEQ ID696, SEQ ID 700, SEQ ID 701, SEQ ID 703, SEQ ID 706, SEQ ID 707, SEQ ID708, SEQ ID 709, SEQ ID 710, SEQ ID 711, SEQ ID 712, SEQ ID 713, SEQ ID714, SEQ ID 717, SEQ ID 718, SEQ ID 719, SEQ ID 720, SEQ ID 721, SEQ ID722, SEQ ID 723, SEQ ID 724, SEQ ID 725, SEQ ID 726, SEQ ID 727, SEQ ID728, SEQ ID 729, SEQ ID 730, SEQ ID 731, SEQ ID 732, SEQ ID 733, SEQ ID734, SEQ ID 736, SEQ ID 737, SEQ ID 738, SEQ ID 739, SEQ ID 740, SEQ ID741, SEQ ID 742, SEQ ID 743, SEQ ID 744, SEQ ID 745, SEQ ID 746, SEQ ID747, SEQ ID 748, SEQ ID 749, SEQ ID 750, SEQ ID 751, SEQ ID 752, SEQ ID753, SEQ ID 756, SEQ ID 758, SEQ ID 759, SEQ ID 760, SEQ ID 761, SEQ ID762, SEQ ID 764, SEQ ID 765, SEQ ID 766, SEQ ID 767, SEQ ID 768, SEQ ID769, SEQ ID 770, SEQ ID 771, SEQ ID 772, SEQ ID 773, SEQ ID 775, SEQ ID776, SEQ ID 777, SEQ ID 778, SEQ ID 779, SEQ ID 780, SEQ ID 782, SEQ ID783, SEQ ID 785, SEQ ID 786, SEQ ID 787, SEQ ID 788, SEQ ID 790, SEQ ID791, SEQ ID 793, SEQ ID 796, SEQ ID 797, SEQ ID 798, SEQ ID 799, SEQ ID800, SEQ ID 801, SEQ ID 802, SEQ ID 803, SEQ ID 804, SEQ ID 805, SEQ ID806, SEQ ID 807, SEQ ID 808, SEQ ID 809, SEQ ID 810, SEQ ID 811, SEQ ID812, SEQ ID 813, SEQ ID 814, SEQ ID 815, SEQ ID 816, SEQ ID 817, SEQ ID818, SEQ ID 819, SEQ ID 820, SEQ ID 821, SEQ ID 822, SEQ ID 823, SEQ ID824, SEQ ID 825, SEQ ID 826, SEQ ID 827, SEQ ID 828, SEQ ID 829, SEQ ID830, SEQ ID 831, SEQ ID 832, SEQ ID 833, SEQ ID 834, SEQ ID 835, SEQ ID836, SEQ ID 837, SEQ ID 838, SEQ ID 839, SEQ ID 840, SEQ ID 841, SEQ ID842, SEQ ID 843, SEQ ID 844, SEQ ID 845, SEQ ID 846, SEQ ID 847, SEQ ID848, SEQ ID 849, SEQ ID 850, SEQ ID 851, SEQ ID 853, SEQ ID 854, SEQ ID855, SEQ ID 856, SEQ ID 857, SEQ ID 859, SEQ ID 861, SEQ ID 862, SEQ ID863, SEQ ID 864, SEQ ID 865, SEQ ID 866, SEQ ID 867, SEQ ID 868, SEQ ID869, SEQ ID 870, SEQ ID 871, SEQ ID 873, SEQ ID 874, SEQ ID 875, SEQ ID876, SEQ ID 877, SEQ ID 878, SEQ ID 879, SEQ ID 880, SEQ ID 881, SEQ ID882, SEQ ID 883, SEQ ID 884, SEQ ID 885, SEQ ID 886, SEQ ID 887, SEQ ID888, SEQ ID 890, SEQ ID 891, SEQ ID 892, SEQ ID 893, SEQ ID 894, SEQ ID895, SEQ ID 896, SEQ ID 897, SEQ ID 898, SEQ ID 899, SEQ ID 900, SEQ ID903, SEQ ID 905, SEQ ID 906, SEQ ID 907, SEQ ID 908, SEQ ID 909, SEQ ID910, SEQ ID 912, SEQ ID 913, SEQ ID 914, SEQ ID 916, SEQ ID 918, SEQ ID919, SEQ ID 921, SEQ ID 922, SEQ ID 923, SEQ ID 925, SEQ ID 926, SEQ ID927, SEQ ID 928, SEQ ID 929, SEQ ID 932, SEQ ID 933, SEQ ID 934, SEQ ID935, SEQ ID 937, SEQ ID 938, SEQ ID 939, SEQ ID 944, SEQ ID 945, SEQ ID946, SEQ ID 947, SEQ ID 948, SEQ ID 949, SEQ ID 950, SEQ ID 951, SEQ ID952, SEQ ID 953, SEQ ID 954, SEQ ID 955, SEQ ID 956, SEQ ID 957, SEQ ID958, SEQ ID 960, SEQ ID 961, SEQ ID 962, SEQ ID 963, SEQ ID 964, SEQ ID965, SEQ ID 966, SEQ ID 967, SEQ ID 968, SEQ ID 969, SEQ ID 970, SEQ ID971, SEQ ID 973, SEQ ID 974, SEQ ID 975, SEQ ID 976, SEQ ID 978, SEQ ID982, SEQ ID 985, SEQ ID 986, SEQ ID 987, SEQ ID 991, SEQ ID 994, SEQ ID995, SEQ ID 996, SEQ ID 997, SEQ ID 998, SEQ ID 999, SEQ ID 1000, SEQ ID1001, SEQ ID 1002, SEQ ID 1003, SEQ ID 1004, SEQ ID 1005, SEQ ID 1006,SEQ ID 1007, SEQ ID 1008, SEQ ID 1009, SEQ ID 1010, SEQ ID 1011, SEQ ID1012, SEQ ID 1013, SEQ ID 1014, SEQ ID 1015, SEQ ID 1016, SEQ ID 1017,SEQ ID 1018, SEQ ID 1019, SEQ ID 1020, SEQ ID 1021, SEQ ID 1022, SEQ ID1023, SEQ ID 1024, SEQ ID 1025, SEQ ID 1026, SEQ ID 1027, SEQ ID 1028,SEQ ID 1030, SEQ ID 1031, SEQ ID 1032, SEQ ID 1033, SEQ ID 1034, SEQ ID1035, SEQ ID 1036, SEQ ID 1037, SEQ ID 1038, SEQ ID 1039, SEQ ID 1040,SEQ ID 1041, SEQ ID 1042, SEQ ID 1043, SEQ ID 1044, SEQ ID 1045, SEQ ID1046, SEQ ID 1047, SEQ ID 1048, SEQ ID 1049, SEQ ID 1050, SEQ ID 1051,SEQ ID 1052, SEQ ID 1053, SEQ ID 1054, SEQ ID 1055, SEQ ID 1056, SEQ ID1057, SEQ ID 1058, SEQ ID 1059, SEQ ID 1060, SEQ ID 1061, SEQ ID 1062,SEQ ID 1063, SEQ ID 1065, SEQ ID 1066, SEQ ID 1067, SEQ ID 1068, SEQ ID1069, SEQ ID 1070, SEQ ID 1071, SEQ ID 1072, SEQ ID 1073, SEQ ID 1074,SEQ ID 1075, SEQ ID 1076, SEQ ID 1077, SEQ ID 1078, SEQ ID 1079, SEQ ID1080, SEQ ID 1081, SEQ ID 1082, SEQ ID 1083, SEQ ID 1084, SEQ ID 1085,SEQ ID 1086, SEQ ID 1087, SEQ ID 1088, SEQ ID 1089, SEQ ID 1090, SEQ ID1091, SEQ ID 1092, SEQ ID 1093, SEQ ID 1094, SEQ ID 1095, SEQ ID 1098,SEQ ID 1099, SEQ ID 1100, SEQ ID 1101, SEQ ID 1102, SEQ ID 1105, SEQ ID1106, SEQ ID 1107, SEQ ID 1108, SEQ ID 1109, SEQ ID 1110, SEQ ID 1111,SEQ ID 1112, SEQ ID 1113, SEQ ID 1114, SEQ ID 1115, SEQ ID 1116, SEQ ID1117, SEQ ID 1118, SEQ ID 1119, SEQ ID 1120, SEQ ID 1121, SEQ ID 1122,SEQ ID 1123, SEQ ID 1124, SEQ ID 1125, SEQ ID 1126, SEQ ID 1127, SEQ ID1128, SEQ ID 1129, SEQ ID 1130, SEQ ID 1131, SEQ ID 1132, SEQ ID 1133,SEQ ID 1134, SEQ ID 1135, SEQ ID 1136, SEQ ID 1137, SEQ ID 1138, SEQ ID1139, SEQ ID 1140, SEQ ID 1141, SEQ ID 1142, SEQ ID 1143, SEQ ID 1144,SEQ ID 1145, SEQ ID 1146, SEQ ID 1147, SEQ ID 1187, SEQ ID 1188, SEQ ID1189, SEQ ID 1190, SEQ ID 1191, SEQ ID 1192, SEQ ID 1193, SEQ ID 1194,SEQ ID 1195, SEQ ID 1196, SEQ ID 1197, SEQ ID 1198, SEQ ID 1199, SEQ ID1200, SEQ ID 1201, SEQ ID 1202, SEQ ID 1203, SEQ ID 1204, SEQ ID 1205,SEQ ID 1206, SEQ ID 1207, SEQ ID 1208, SEQ ID 1209, SEQ ID 1210, SEQ ID1211, SEQ ID 1212, SEQ ID 1213, SEQ ID 1214, SEQ ID 1215, SEQ ID 1216,SEQ ID 1217, SEQ ID 1219, SEQ ID 1220, SEQ ID 1221, SEQ ID 1222, SEQ ID1223, SEQ ID 1224, SEQ ID 1225, SEQ ID 1226, SEQ ID 1227, SEQ ID 1230,SEQ ID 1231, SEQ ID 1232, SEQ ID 1233, SEQ ID 1234, SEQ ID 1235, SEQ ID1236, SEQ ID 1237, SEQ ID 1238, SEQ ID 1239, SEQ ID 1240, SEQ ID 1241,SEQ ID 1242, SEQ ID 1243, SEQ ID 1244, SEQ ID 1245, SEQ ID 1246, SEQ ID1247, SEQ ID 1248, SEQ ID 1250, SEQ ID 1251, SEQ ID 1252, SEQ ID 1253,SEQ ID 1254, SEQ ID 1255, SEQ ID 1256, SEQ ID 1257, SEQ ID 1258, SEQ ID1259, SEQ ID 1260, SEQ ID 1261, SEQ ID 1262, SEQ ID 1263, SEQ ID 1264,SEQ ID 1265, SEQ ID 1266, SEQ ID 1267, SEQ ID 1268, SEQ ID 1269, SEQ ID1270, SEQ ID 1271, SEQ ID 1272, SEQ ID 1273, SEQ ID 1274, SEQ ID 1275,SEQ ID 1276, SEQ ID 1277, SEQ ID 1278, SEQ ID 1279, SEQ ID 1280, SEQ ID1281, SEQ ID 1282, SEQ ID 1283, SEQ ID 1284, SEQ ID 1285, SEQ ID 1286,SEQ ID 1287, SEQ ID 1288, SEQ ID 1289, SEQ ID 1290, SEQ ID 1291, SEQ ID1292, SEQ ID 1293, SEQ ID 1294, SEQ ID 1295, SEQ ID 1296, SEQ ID 1297,SEQ ID 1298, SEQ ID 1299, SEQ ID 1300, SEQ ID 1301, SEQ ID 1302, SEQ ID1303, SEQ ID 1304, SEQ ID 1306, SEQ ID 1307, SEQ ID 1308, SEQ ID 1309,SEQ ID 1310, SEQ ID 1311, SEQ ID 1312, SEQ ID 1313, SEQ ID 1314, SEQ ID1315, SEQ ID 1316, SEQ ID 1317, SEQ ID 1318, SEQ ID 1319, SEQ ID 1320,SEQ ID 1321, SEQ ID 1322, SEQ ID 1323, SEQ ID 1325, SEQ ID 1326, SEQ ID1327, SEQ ID 1328, SEQ ID 1329, SEQ ID 1330, SEQ ID 1332, SEQ ID 1333,SEQ ID 1335, SEQ ID 1336, SEQ ID 1337, SEQ ID 1338, SEQ ID 1339, SEQ ID1341, SEQ ID 1342, SEQ ID 1343, SEQ ID 1344, SEQ ID 1345, SEQ ID 1346,SEQ ID 1347, SEQ ID 1348, SEQ ID 1349, SEQ ID 1350, SEQ ID 1351, SEQ ID1352, SEQ ID 1353, SEQ ID 1354, SEQ ID 1355, SEQ ID 1356, SEQ ID 1357,SEQ ID 1425, SEQ ID 1426, SEQ ID 1427, SEQ ID 1428, SEQ ID 1429, SEQ ID1430, SEQ ID 1431, SEQ ID 1432, SEQ ID 1433, SEQ ID 1434, SEQ ID 1435,SEQ ID 1436, SEQ ID 1437, SEQ ID 1438, SEQ ID 1440, SEQ ID 1441, SEQ ID1442, SEQ ID 1443, SEQ ID 1444, SEQ ID 1445, SEQ ID 1446, SEQ ID 1447,SEQ ID 1448, SEQ ID 1449, SEQ ID 1450, SEQ ID 1451, SEQ ID 1452, SEQ ID1453, SEQ ID 1454, SEQ ID 1455, SEQ ID 1456, SEQ ID 1457, SEQ ID 1458,SEQ ID 1459, SEQ ID 1460, SEQ ID 1461, SEQ ID 1462, SEQ ID 1463, SEQ ID1464, SEQ ID 1465, SEQ ID 1466, SEQ ID 1467, SEQ ID 1469, SEQ ID 1470,SEQ ID 1471, SEQ ID 1472, SEQ ID 1474, SEQ ID 1475, SEQ ID 1476, SEQ ID1477, SEQ ID 1478, SEQ ID 1479, SEQ ID 1480, SEQ ID 1481, SEQ ID 1482,SEQ ID 1484, SEQ ID 1485, SEQ ID 1487, SEQ ID 1488, SEQ ID 1489, SEQ ID1491, SEQ ID 1492, SEQ ID 1493, SEQ ID 1494, SEQ ID 1495, SEQ ID 1496,SEQ ID 1497, SEQ ID 1498, SEQ ID 1499, SEQ ID 1500, SEQ ID 1501, SEQ ID1502, SEQ ID 1503, SEQ ID 1504, SEQ ID 1505, SEQ ID 1506, SEQ ID 1507,SEQ ID 1508, SEQ ID 1509, SEQ ID 1510, SEQ ID 1511, SEQ ID 1512, SEQ ID1513, SEQ ID 1514, SEQ ID 1515, SEQ ID 1516, SEQ ID 1517, SEQ ID 1518,SEQ ID 1519, SEQ ID 1520, SEQ ID 1521, SEQ ID 1522, SEQ ID 1523, SEQ ID1524, SEQ ID 1525, SEQ ID 1526, SEQ ID 1527, SEQ ID 1528, SEQ ID 1529,SEQ ID 1530, SEQ ID 1531, SEQ ID 1532, SEQ ID 1533, SEQ ID 1534, SEQ ID1535, SEQ ID 1536, SEQ ID 1537, SEQ ID 1538, SEQ ID 1539, SEQ ID 1540,SEQ ID 1541, SEQ ID 1542, SEQ ID 1543, SEQ ID 1544, SEQ ID 1545, SEQ ID1546, SEQ ID 1547, SEQ ID 1548, SEQ ID 1549, SEQ ID 1550, SEQ ID 1551,SEQ ID 1552, SEQ ID 1553, SEQ ID 1554, SEQ ID 1555, SEQ ID 1556, SEQ ID1557, SEQ ID 1558, SEQ ID 1559, SEQ ID 1560, SEQ ID 1561, SEQ ID 1562,SEQ ID 1563, SEQ ID 1564, SEQ ID 1565, SEQ ID 1566, SEQ ID 1567, SEQ ID1568, SEQ ID 1569, SEQ ID 1570, SEQ ID 1571, SEQ ID 1572, SEQ ID 1573,SEQ ID 1574, SEQ ID 1575, SEQ ID 1576, SEQ ID 1577, SEQ ID 1578, SEQ ID1579, SEQ ID 1580, SEQ ID 1581, SEQ ID 1582, SEQ ID 1583, SEQ ID 1584,SEQ ID 1585, SEQ ID 1586, SEQ ID 1587, SEQ ID 1588, SEQ ID 1589, SEQ ID1590, SEQ ID 1591, SEQ ID 1592, SEQ ID 1593, SEQ ID 1594, SEQ ID 1595,SEQ ID 1596, SEQ ID 1597, SEQ ID 1598, SEQ ID 1599, SEQ ID 1600, SEQ ID1601, SEQ ID 1602, SEQ ID 1603, SEQ ID 1604, SEQ ID 1605, SEQ ID 1606,SEQ ID 1607, SEQ ID 1608, SEQ ID 1609, SEQ ID 1610, SEQ ID 1611, SEQ ID1612, SEQ ID 1613, SEQ ID 1614, SEQ ID 1615, SEQ ID 1616, SEQ ID 1617,SEQ ID 1618, SEQ ID 1620, SEQ ID 1621, SEQ ID 1622, SEQ ID 1623, SEQ ID1624, SEQ ID 1625, SEQ ID 1626, SEQ ID 1627, SEQ ID 1628, SEQ ID 1629,SEQ ID 1630, SEQ ID 1631, SEQ ID 1632, SEQ ID 1633, SEQ ID 1634, SEQ ID1635, SEQ ID 1636, SEQ ID 1637, SEQ ID 1638, SEQ ID 1639, SEQ ID 1640,SEQ ID 1641, SEQ ID 1642, SEQ ID 1643, SEQ ID 1644, SEQ ID 1645, SEQ ID1647, SEQ ID 1648, SEQ ID 1649, SEQ ID 1650, SEQ ID 1651, SEQ ID 1652,SEQ ID 1654, SEQ ID 1656, SEQ ID 1657, SEQ ID 1658, SEQ ID 1659, SEQ ID1660, SEQ ID 1661, SEQ ID 1663, SEQ ID 1664, SEQ ID 1665, SEQ ID 1666,SEQ ID 1667, SEQ ID 1668, SEQ ID 1669, SEQ ID 1670, SEQ ID 1671, SEQ ID1672, SEQ ID 1673, SEQ ID 1674, SEQ ID 1675, SEQ ID 1676, SEQ ID 1677,SEQ ID 1678, SEQ ID 1679, SEQ ID 1680, SEQ ID 1681, SEQ ID 1682, SEQ ID1683, SEQ ID 1684, SEQ ID 1685, SEQ ID 1686, SEQ ID 1687, SEQ ID 1688,SEQ ID 1689, SEQ ID 1690, SEQ ID 1692, SEQ ID 1693, SEQ ID 1694, SEQ ID1695, SEQ ID 1696, SEQ ID 1697, SEQ ID 1698, SEQ ID 1699, SEQ ID 1701,SEQ ID 1703, SEQ ID 1704, SEQ ID 1705, SEQ ID 1706, SEQ ID 1707, SEQ ID1708, SEQ ID 1709, SEQ ID 1710, SEQ ID 1711, SEQ ID 1712, SEQ ID 1714,SEQ ID 1715, SEQ ID 1716, SEQ ID 1717, SEQ ID 1718, SEQ ID 1719, SEQ ID1720, SEQ ID 1721, SEQ ID 1722, SEQ ID 1723, SEQ ID 1724, SEQ ID 1725,SEQ ID 1726, SEQ ID 1727, SEQ ID 1728, SEQ ID 1729, SEQ ID 1730, SEQ ID1731, SEQ ID 1732, SEQ ID 1733, SEQ ID 1734, SEQ ID 1735, SEQ ID 1736,SEQ ID 1737, SEQ ID 1738, SEQ ID 1739, SEQ ID 1740, SEQ ID 1741, SEQ ID1742, SEQ ID 1743, SEQ ID 1762, SEQ ID 1763, SEQ ID 1764, SEQ ID 1765,SEQ ID 1766, SEQ ID 1767, SEQ ID 1768, SEQ ID 1769, SEQ ID 1770, SEQ ID1771, SEQ ID 1772, SEQ ID 1773, SEQ ID 1774, SEQ ID 1775, SEQ ID 1776,SEQ ID 1777, SEQ ID 1778, SEQ ID 1779, SEQ ID 1780, SEQ ID 1781, SEQ ID1782, SEQ ID 1783, SEQ ID 1784, SEQ ID 1785, SEQ ID 1786, SEQ ID 1787,SEQ ID 1788, SEQ ID 1789, SEQ ID 1790, SEQ ID 1791, SEQ ID 1792, SEQ ID1793, SEQ ID 1794, SEQ ID 1795, SEQ ID 1796, SEQ ID 1797, SEQ ID 1798,SEQ ID 1799, SEQ ID 1800, SEQ ID 1801, SEQ ID 1802, SEQ ID 1803, SEQ ID1804, SEQ ID 1805, SEQ ID 1806, SEQ ID 1807, SEQ ID 1808, SEQ ID 1809,SEQ ID 1810, SEQ ID 1811, SEQ ID 1812, SEQ ID 1813, SEQ ID 1814, SEQ ID1815, SEQ ID 1816, SEQ ID 1817, SEQ ID 1818, SEQ ID 1819, SEQ ID 1820,SEQ ID 1821, SEQ ID 1822, SEQ ID 1823, SEQ ID 1824, SEQ ID 1825, SEQ ID1826, SEQ ID 1832, SEQ ID 1833, SEQ ID 1836, SEQ ID 1837, SEQ ID 1838,SEQ ID 1839, SEQ ID 1840, SEQ ID 1858, SEQ ID 1859, SEQ ID 1860, SEQ ID1861, SEQ ID 1862, SEQ ID 1863, SEQ ID 1865, SEQ ID 1866, SEQ ID 1868,SEQ ID 1869, SEQ ID 1873, SEQ ID 1877, SEQ ID 1880, SEQ ID 1883, SEQ ID1884, SEQ ID 1888, SEQ ID 1889, SEQ ID 1890, SEQ ID 1893, SEQ ID 1894,SEQ ID 1895, SEQ ID 1896, SEQ ID 1897, SEQ ID 1898, SEQ ID 1899, SEQ ID1900, SEQ ID 1902, SEQ ID 1903, SEQ ID 1904, SEQ ID 1906, SEQ ID 1907,SEQ ID 1908, SEQ ID 1910, SEQ ID 1911, SEQ ID 1913, SEQ ID 1914, SEQ ID1915, SEQ ID 1916, SEQ ID 1918, SEQ ID 1920, SEQ ID 1921, SEQ ID 1922,SEQ ID 1924, SEQ ID 1928, SEQ ID 1929, SEQ ID 1930, SEQ ID 1932, SEQ ID1933, SEQ ID 1938, SEQ ID 1939, SEQ ID 1940, SEQ ID 1941, SEQ ID 1943,SEQ ID 1944, SEQ ID 1945, SEQ ID 1946, SEQ ID 1948, SEQ ID 1949, SEQ ID1950, SEQ ID 1952, SEQ ID 1953, SEQ ID 1956, SEQ ID 1957, SEQ ID 1958,SEQ ID 1960, SEQ ID 1962, SEQ ID 1964, SEQ ID 1966, SEQ ID 1967, SEQ ID1970, SEQ ID 1971, SEQ ID 1972, SEQ ID 1973, SEQ ID 1974, SEQ ID 1975,SEQ ID 1977, SEQ ID 1979, SEQ ID 1981, SEQ ID 1982, SEQ ID 1985, SEQ ID1986, SEQ ID 1987, SEQ ID 1988, SEQ ID 1989, SEQ ID 1993, SEQ ID 1995,SEQ ID 1996, SEQ ID 1997, SEQ ID 1998, SEQ ID 1999, SEQ ID 2000, SEQ ID2001, SEQ ID 2002, SEQ ID 2003, SEQ ID 2004, SEQ ID 2005, SEQ ID 2008,SEQ ID 2009, SEQ ID 2010, SEQ ID 2011, SEQ ID 2013, SEQ ID 2014, SEQ ID2015, SEQ ID 2017, SEQ ID 2019, SEQ ID 2020, SEQ ID 2021, SEQ ID 2023,SEQ ID 2026, SEQ ID 2028, SEQ ID 2031, SEQ ID 2032, SEQ ID 2033, SEQ ID2035, SEQ ID 2036, SEQ ID 2037, SEQ ID 2038, SEQ ID 2042, SEQ ID 2044,SEQ ID 2048, SEQ ID 2050, SEQ ID 2051, SEQ ID 2052, SEQ ID 2053, SEQ ID2054, SEQ ID 2055, SEQ ID 2056, SEQ ID 2057, SEQ ID 2058, SEQ ID 2059,SEQ ID 2060, SEQ ID 2061, SEQ ID 2062, SEQ ID 2063, SEQ ID 2064, SEQ ID2065, SEQ ID 2066, SEQ ID 2067, SEQ ID 2068, SEQ ID 2069, SEQ ID 2070,SEQ ID 2071, SEQ ID 2072, SEQ ID 2073, SEQ ID 2074, SEQ ID 2075, SEQ ID2076, SEQ ID 2077, SEQ ID 2078, SEQ ID 2079, SEQ ID 2080, SEQ ID 2081,SEQ ID 2082, SEQ ID 2083, SEQ ID 2084, SEQ ID 2085, SEQ ID 2086, SEQ ID2087, SEQ ID 2088, SEQ ID 2089, SEQ ID 2090, SEQ ID 2091, SEQ ID 2092,SEQ ID 2093, SEQ ID 2094, SEQ ID 2095, SEQ ID 2096, SEQ ID 2097, SEQ ID2098, SEQ ID 2099, SEQ ID 2101, SEQ ID 2102, SEQ ID 2103, SEQ ID 2104,SEQ ID 2105, SEQ ID 2106, SEQ ID 2107, SEQ ID 2108, SEQ ID 2109, SEQ ID2110, SEQ ID 2111, SEQ ID 2112, SEQ ID 2113, SEQ ID 2114, SEQ ID 2115,SEQ ID 2116, SEQ ID 2117, SEQ ID 2118, SEQ ID 2119, SEQ ID 2120, SEQ ID2121, SEQ ID 2122, SEQ ID 2123, SEQ ID 2124, SEQ ID 2125, SEQ ID 2126,SEQ ID 2127, SEQ ID 2146, SEQ ID 2147, SEQ ID 2148, SEQ ID 2149, SEQ ID2150, SEQ ID 2151, SEQ ID 2152, SEQ ID 2153, SEQ ID 2154, SEQ ID 2155,SEQ ID 2156, SEQ ID 2157, SEQ ID 2158, SEQ ID 2159, SEQ ID 2160, SEQ ID2161, SEQ ID 2162, SEQ ID 2163, SEQ ID 2164, SEQ ID 2165, SEQ ID 2166,SEQ ID 2167, SEQ ID 2168, SEQ ID 2169, SEQ ID 2170, SEQ ID 2171, SEQ ID2172, SEQ ID 2173, SEQ ID 2174, SEQ ID 2175, SEQ ID 2176, SEQ ID 2177,SEQ ID 2178, SEQ ID 2179, SEQ ID 2180, SEQ ID 2181, SEQ ID 2182, SEQ ID2183, SEQ ID 2184, SEQ ID 2185, SEQ ID 2186, SEQ ID 2187, SEQ ID 2188,SEQ ID 2189, SEQ ID 2190, SEQ ID 2191, SEQ ID 2192, SEQ ID 2193, SEQ ID2194, SEQ ID 2195, SEQ ID 2196, SEQ ID 2197, SEQ ID 2198, SEQ ID 2199,SEQ ID 2200, SEQ ID 2201, SEQ ID 2202, SEQ ID 2203, SEQ ID 2204, SEQ ID2205, SEQ ID 2206, SEQ ID 2207, SEQ ID 2208, SEQ ID 2209, SEQ ID 2210,SEQ ID 2211, SEQ ID 2212, SEQ ID 2213, SEQ ID 2214, SEQ ID 2216, SEQ ID2220, SEQ ID 2222, SEQ ID 2223, SEQ ID 2224, SEQ ID 2225, SEQ ID 2239,SEQ ID 2240, SEQ ID 2241, SEQ ID 2242, SEQ ID 2243, SEQ ID 2244, SEQ ID2245, SEQ ID 2246, SEQ ID 2247, SEQ ID 2248, SEQ ID 2249, SEQ ID 2250,SEQ ID 2251, SEQ ID 2252, SEQ ID 2253, SEQ ID 2254, SEQ ID 2255, SEQ ID2256, SEQ ID 2257, SEQ ID 2258, SEQ ID 2259, SEQ ID 2260, SEQ ID 2261,SEQ ID 2262, SEQ ID 2263, SEQ ID 2264, SEQ ID 2265, SEQ ID 2266, SEQ ID2267, SEQ ID 2268, SEQ ID 2269, SEQ ID 2270, SEQ ID 2271, SEQ ID 2272,SEQ ID 2273, SEQ ID 2274, SEQ ID 2275, SEQ ID 2276, SEQ ID 2277, SEQ ID2278, SEQ ID 2279, SEQ ID 2280, SEQ ID 2281, SEQ ID 2282, SEQ ID 2283,SEQ ID 2284, SEQ ID 2285, SEQ ID 2286, SEQ ID 2287, SEQ ID 2288, SEQ ID2289, SEQ ID 2290, SEQ ID 2291, SEQ ID 2292, SEQ ID 2293, SEQ ID 2294,SEQ ID 2295, SEQ ID 2296, SEQ ID 2297, SEQ ID 2298, SEQ ID 2299, SEQ ID2300, SEQ ID 2301, SEQ ID 2302, SEQ ID 2303, SEQ ID 2304, SEQ ID 2305,SEQ ID 2306, SEQ ID 2307, SEQ ID 2308, SEQ ID 2309, SEQ ID 2310, SEQ ID2311, SEQ ID 2312, SEQ ID 2313, SEQ ID 2314, SEQ ID 2315, SEQ ID 2316,SEQ ID 2317, SEQ ID 2318, SEQ ID 2319, and SEQ ID 2320.

In some embodiments, the antisense oligonucleotide progranulin agonistis selected from the group consisting of SEQ ID 693, SEQ ID 707, SEQ ID708, SEQ ID 709, SEQ ID 710, SEQ ID 711, SEQ ID 720, SEQ ID 721, SEQ ID723, SEQ ID 724, SEQ ID 725, SEQ ID 726, SEQ ID 727, SEQ ID 730, SEQ ID732, SEQ ID 736, SEQ ID 737, SEQ ID 738, SEQ ID 739, SEQ ID 741, SEQ ID743, SEQ ID 745, SEQ ID 747, SEQ ID 758, SEQ ID 759, SEQ ID 760, SEQ ID761, SEQ ID 766, SEQ ID 775, SEQ ID 798, SEQ ID 800, SEQ ID 801, SEQ ID802, SEQ ID 803, SEQ ID 804, SEQ ID 807, SEQ ID 812, SEQ ID 813, SEQ ID814, SEQ ID 816, SEQ ID 818, SEQ ID 819, SEQ ID 822, SEQ ID 823, SEQ ID824, SEQ ID 825, SEQ ID 826, SEQ ID 827, SEQ ID 828, SEQ ID 830, SEQ ID831, SEQ ID 833, SEQ ID 835, SEQ ID 836, SEQ ID 837, SEQ ID 838, SEQ ID839, SEQ ID 840, SEQ ID 841, SEQ ID 842, SEQ ID 843, SEQ ID 844, SEQ ID845, SEQ ID 846, SEQ ID 847, SEQ ID 848, SEQ ID 849, SEQ ID 850, SEQ ID854, SEQ ID 855, SEQ ID 856, SEQ ID 857, SEQ ID 859, SEQ ID 861, SEQ ID866, SEQ ID 867, SEQ ID 868, SEQ ID 869, SEQ ID 871, SEQ ID 873, SEQ ID874, SEQ ID 876, SEQ ID 878, SEQ ID 879, SEQ ID 880, SEQ ID 881, SEQ ID883, SEQ ID 885, SEQ ID 887, SEQ ID 888, SEQ ID 890, SEQ ID 891, SEQ ID892, SEQ ID 893, SEQ ID 895, SEQ ID 897, SEQ ID 906, SEQ ID 909, SEQ ID916, SEQ ID 918, SEQ ID 926, SEQ ID 927, SEQ ID 928, SEQ ID 932, SEQ ID933, SEQ ID 934, SEQ ID 967, SEQ ID 998, SEQ ID 1000, SEQ ID 1001, SEQID 1002, SEQ ID 1003, SEQ ID 1005, SEQ ID 1010, SEQ ID 1011, SEQ ID1012, SEQ ID 1021, SEQ ID 1023, SEQ ID 1024, SEQ ID 1027, SEQ ID 1030,SEQ ID 1037, SEQ ID 1038, SEQ ID 1039, SEQ ID 1041, SEQ ID 1042, SEQ ID1048, SEQ ID 1049, SEQ ID 1050, SEQ ID 1051, SEQ ID 1054, SEQ ID 1058,SEQ ID 1060, SEQ ID 1061, SEQ ID 1063, SEQ ID 1066, SEQ ID 1070, SEQ ID1071, SEQ ID 1072, SEQ ID 1073, SEQ ID 1075, SEQ ID 1078, SEQ ID 1081,SEQ ID 1083, SEQ ID 1084, SEQ ID 1085, SEQ ID 1086, SEQ ID 1091, SEQ ID1092, SEQ ID 1093, SEQ ID 1109, SEQ ID 1111, SEQ ID 1112, SEQ ID 1113,SEQ ID 1114, SEQ ID 1115, SEQ ID 1116, SEQ ID 1117, SEQ ID 1118, SEQ ID1119, SEQ ID 1120, SEQ ID 1121, SEQ ID 1122, SEQ ID 1123, SEQ ID 1124,SEQ ID 1125, SEQ ID 1126, SEQ ID 1127, SEQ ID 1128, SEQ ID 1129, SEQ ID1130, SEQ ID 1132, SEQ ID 1135, SEQ ID 1136, SEQ ID 1137, SEQ ID 1138,SEQ ID 1139, SEQ ID 1140, SEQ ID 1141, SEQ ID 1142, SEQ ID 1143, SEQ ID1144, SEQ ID 1146, SEQ ID 1188, SEQ ID 1189, SEQ ID 1190, SEQ ID 1191,SEQ ID 1192, SEQ ID 1196, SEQ ID 1200, SEQ ID 1201, SEQ ID 1202, SEQ ID1203, SEQ ID 1204, SEQ ID 1205, SEQ ID 1206, SEQ ID 1207, SEQ ID 1208,SEQ ID 1209, SEQ ID 1223, SEQ ID 1224, SEQ ID 1238, SEQ ID 1243, SEQ ID1244, SEQ ID 1258, SEQ ID 1259, SEQ ID 1262, SEQ ID 1263, SEQ ID 1264,SEQ ID 1267, SEQ ID 1268, SEQ ID 1271, SEQ ID 1276, SEQ ID 1282, SEQ ID1283, SEQ ID 1284, SEQ ID 1285, SEQ ID 1286, SEQ ID 1288, SEQ ID 1290,SEQ ID 1291, SEQ ID 1292, SEQ ID 1294, SEQ ID 1297, SEQ ID 1298, SEQ ID1304, SEQ ID 1311, SEQ ID 1313, SEQ ID 1314, SEQ ID 1315, SEQ ID 1344,SEQ ID 1345, SEQ ID 1346, SEQ ID 1347, SEQ ID 1348, SEQ ID 1349, SEQ ID1352, SEQ ID 1355, SEQ ID 1357, SEQ ID 1425, SEQ ID 1426, SEQ ID 1427,SEQ ID 1428, SEQ ID 1430, SEQ ID 1431, SEQ ID 1432, SEQ ID 1433, SEQ ID1434, SEQ ID 1435, SEQ ID 1436, SEQ ID 1437, SEQ ID 1438, SEQ ID 1440,SEQ ID 1441, SEQ ID 1442, SEQ ID 1443, SEQ ID 1444, SEQ ID 1445, SEQ ID1446, SEQ ID 1447, SEQ ID 1448, SEQ ID 1449, SEQ ID 1450, SEQ ID 1451,SEQ ID 1454, SEQ ID 1455, SEQ ID 1456, SEQ ID 1457, SEQ ID 1460, SEQ ID1461, SEQ ID 1462, SEQ ID 1463, SEQ ID 1464, SEQ ID 1467, SEQ ID 1469,SEQ ID 1474, SEQ ID 1478, SEQ ID 1480, SEQ ID 1482, SEQ ID 1488, SEQ ID1492, SEQ ID 1493, SEQ ID 1497, SEQ ID 1498, SEQ ID 1505, SEQ ID 1506,SEQ ID 1507, SEQ ID 1509, SEQ ID 1510, SEQ ID 1512, SEQ ID 1513, SEQ ID1514, SEQ ID 1515, SEQ ID 1517, SEQ ID 1520, SEQ ID 1524, SEQ ID 1525,SEQ ID 1528, SEQ ID 1529, SEQ ID 1530, SEQ ID 1531, SEQ ID 1532, SEQ ID1533, SEQ ID 1534, SEQ ID 1535, SEQ ID 1536, SEQ ID 1537, SEQ ID 1538,SEQ ID 1539, SEQ ID 1540, SEQ ID 1541, SEQ ID 1542, SEQ ID 1544, SEQ ID1545, SEQ ID 1546, SEQ ID 1547, SEQ ID 1548, SEQ ID 1549, SEQ ID 1550,SEQ ID 1551, SEQ ID 1552, SEQ ID 1553, SEQ ID 1554, SEQ ID 1555, SEQ ID1556, SEQ ID 1558, SEQ ID 1560, SEQ ID 1563, SEQ ID 1565, SEQ ID 1568,SEQ ID 1569, SEQ ID 1575, SEQ ID 1577, SEQ ID 1578, SEQ ID 1579, SEQ ID1582, SEQ ID 1583, SEQ ID 1584, SEQ ID 1585, SEQ ID 1586, SEQ ID 1587,SEQ ID 1588, SEQ ID 1589, SEQ ID 1590, SEQ ID 1591, SEQ ID 1593, SEQ ID1594, SEQ ID 1595, SEQ ID 1596, SEQ ID 1599, SEQ ID 1608, SEQ ID 1609,SEQ ID 1610, SEQ ID 1611, SEQ ID 1612, SEQ ID 1613, SEQ ID 1614, SEQ ID1615, SEQ ID 1616, SEQ ID 1617, SEQ ID 1618, SEQ ID 1620, SEQ ID 1621,SEQ ID 1622, SEQ ID 1623, SEQ ID 1624, SEQ ID 1626, SEQ ID 1630, SEQ ID1631, SEQ ID 1633, SEQ ID 1635, SEQ ID 1637, SEQ ID 1638, SEQ ID 1639,SEQ ID 1643, SEQ ID 1644, SEQ ID 1645, SEQ ID 1648, SEQ ID 1649, SEQ ID1651, SEQ ID 1658, SEQ ID 1667, SEQ ID 1669, SEQ ID 1677, SEQ ID 1679,SEQ ID 1681, SEQ ID 1684, SEQ ID 1685, SEQ ID 1686, SEQ ID 1688, SEQ ID1689, SEQ ID 1690, SEQ ID 1692, SEQ ID 1704, SEQ ID 1707, SEQ ID 1708,SEQ ID 1709, SEQ ID 1710, SEQ ID 1711, SEQ ID 1712, SEQ ID 1714, SEQ ID1715, SEQ ID 1717, SEQ ID 1718, SEQ ID 1719, SEQ ID 1720, SEQ ID 1721,SEQ ID 1722, SEQ ID 1723, SEQ ID 1724, SEQ ID 1725, SEQ ID 1726, SEQ ID1727, SEQ ID 1728, SEQ ID 1731, SEQ ID 1732, SEQ ID 1733, SEQ ID 1734,SEQ ID 1735, SEQ ID 1736, SEQ ID 1737, SEQ ID 1738, SEQ ID 1741, SEQ ID1742, SEQ ID 1762, SEQ ID 1764, SEQ ID 1765, SEQ ID 1766, SEQ ID 1767,SEQ ID 1768, SEQ ID 1769, SEQ ID 1770, SEQ ID 1771, SEQ ID 1773, SEQ ID1775, SEQ ID 1776, SEQ ID 1779, SEQ ID 1780, SEQ ID 1781, SEQ ID 1782,SEQ ID 1783, SEQ ID 1784, SEQ ID 1785, SEQ ID 1786, SEQ ID 1787, SEQ ID1789, SEQ ID 1791, SEQ ID 1792, SEQ ID 1794, SEQ ID 1795, SEQ ID 1796,SEQ ID 1800, SEQ ID 1801, SEQ ID 1802, SEQ ID 1804, SEQ ID 1805, SEQ ID1806, SEQ ID 1807, SEQ ID 1808, SEQ ID 1809, SEQ ID 1811, SEQ ID 1812,SEQ ID 1813, SEQ ID 1814, SEQ ID 1815, SEQ ID 1816, SEQ ID 1817, SEQ ID1818, SEQ ID 1819, SEQ ID 1820, SEQ ID 1821, SEQ ID 1822, SEQ ID 1823,SEQ ID 1824, SEQ ID 1832, SEQ ID 1833, SEQ ID 1838, SEQ ID 1839, SEQ ID1840, SEQ ID 1862, SEQ ID 1866, SEQ ID 1868, SEQ ID 1873, SEQ ID 1877,SEQ ID 1883, SEQ ID 1884, SEQ ID 1888, SEQ ID 1889, SEQ ID 1893, SEQ ID1894, SEQ ID 1928, SEQ ID 1929, SEQ ID 1933, SEQ ID 1938, SEQ ID 1939,SEQ ID 1940, SEQ ID 1941, SEQ ID 1943, SEQ ID 1944, SEQ ID 1948, SEQ ID1950, SEQ ID 1952, SEQ ID 1956, SEQ ID 1966, SEQ ID 1985, SEQ ID 1986,SEQ ID 1996, SEQ ID 1997, SEQ ID 1998, SEQ ID 1999, SEQ ID 2000, SEQ ID2005, SEQ ID 2013, SEQ ID 2015, SEQ ID 2020, SEQ ID 2023, SEQ ID 2026,SEQ ID 2028, SEQ ID 2031, SEQ ID 2032, SEQ ID 2033, SEQ ID 2042, SEQ ID2048, SEQ ID 2052, SEQ ID 2053, SEQ ID 2055, SEQ ID 2056, SEQ ID 2057,SEQ ID 2058, SEQ ID 2059, SEQ ID 2060, SEQ ID 2061, SEQ ID 2063, SEQ ID2065, SEQ ID 2066, SEQ ID 2067, SEQ ID 2068, SEQ ID 2070, SEQ ID 2072,SEQ ID 2073, SEQ ID 2075, SEQ ID 2076, SEQ ID 2079, SEQ ID 2080, SEQ ID2081, SEQ ID 2082, SEQ ID 2083, SEQ ID 2084, SEQ ID 2085, SEQ ID 2086,SEQ ID 2087, SEQ ID 2088, SEQ ID 2089, SEQ ID 2090, SEQ ID 2091, SEQ ID2092, SEQ ID 2093, SEQ ID 2094, SEQ ID 2095, SEQ ID 2097, SEQ ID 2116,SEQ ID 2119, SEQ ID 2120, SEQ ID 2121, SEQ ID 2122, SEQ ID 2123, SEQ ID2124, SEQ ID 2125, SEQ ID 2126, SEQ ID 2127, SEQ ID 2146, SEQ ID 2147,SEQ ID 2148, SEQ ID 2158, SEQ ID 2160, SEQ ID 2162, SEQ ID 2163, SEQ ID2165, SEQ ID 2166, SEQ ID 2167, SEQ ID 2168, SEQ ID 2169, SEQ ID 2170,SEQ ID 2171, SEQ ID 2172, SEQ ID 2173, SEQ ID 2174, SEQ ID 2175, SEQ ID2176, SEQ ID 2177, SEQ ID 2181, SEQ ID 2182, SEQ ID 2183, SEQ ID 2184,SEQ ID 2185, SEQ ID 2186, SEQ ID 2187, SEQ ID 2193, SEQ ID 2194, SEQ ID2195, SEQ ID 2196, SEQ ID 2197, SEQ ID 2198, SEQ ID 2199, SEQ ID 2200,SEQ ID 2202, SEQ ID 2203, SEQ ID 2204, SEQ ID 2206, SEQ ID 2208, SEQ ID2209, SEQ ID 2210, SEQ ID 2211, SEQ ID 2212, SEQ ID 2213, SEQ ID 2214,SEQ ID 2216, SEQ ID 2222, SEQ ID 2224, SEQ ID 2239, SEQ ID 2240, SEQ ID2242, SEQ ID 2243, SEQ ID 2244, SEQ ID 2245, SEQ ID 2246, SEQ ID 2247,SEQ ID 2248, SEQ ID 2251, SEQ ID 2252, SEQ ID 2253, SEQ ID 2254, SEQ ID2255, SEQ ID 2256, SEQ ID 2257, SEQ ID 2258, SEQ ID 2259, SEQ ID 2260,SEQ ID 2261, SEQ ID 2262, SEQ ID 2263, SEQ ID 2264, SEQ ID 2265, SEQ ID2266, SEQ ID 2267, SEQ ID 2268, SEQ ID 2269, SEQ ID 2280, SEQ ID 2281,SEQ ID 2282, SEQ ID 2283, SEQ ID 2284, SEQ ID 2285, SEQ ID 2294, SEQ ID2295, SEQ ID 2302, SEQ ID 2307, SEQ ID 2308, SEQ ID 2309, SEQ ID 2310,SEQ ID 2311, SEQ ID 2312, SEQ ID 2316, SEQ ID 2317, SEQ ID 2318, SEQ ID2319, and SEQ ID 2320.

The invention provides for a conjugate comprising the antisenseoligonucleotide progranulin agonist according to the invention, and atleast one conjugate moiety covalently attached to said antisenseoligonucleotide progranulin agonist.

The invention provides an antisense oligonucleotide progranulin agonistcovalently attached to at least one conjugate moiety.

The invention provides for a pharmaceutically acceptable salt of theantisense oligonucleotide progranulin agonist according to theinvention, or the conjugate according to the invention.

The invention provides for an antisense oligonucleotide progranulinagonist according to the invention wherein the antisense oligonucleotideprogranulin agonist is in the form of a pharmaceutically acceptablesalt. In some embodiments the pharmaceutically acceptable salt may be asodium salt or a potassium salt.

The invention provides for a pharmaceutically acceptable sodium salt ofthe antisense oligonucleotide progranulin agonist according to theinvention, or the conjugate according to the invention.

The invention provides for a pharmaceutically acceptable potassium saltof the antisense oligonucleotide progranulin agonist according to theinvention, or the conjugate according to the invention.

The invention provides for a pharmaceutical composition comprising theantisense oligonucleotide progranulin agonist of the invention, or theconjugate of the invention, and a pharmaceutically acceptable diluent,solvent, carrier, salt and/or adjuvant.

The invention provides for a pharmaceutical composition comprising theantisense oligonucleotide progranulin agonist of the invention, or theconjugate of the invention, and a pharmaceutically acceptable salt. Forexample, the salt may comprise a metal cation, such as a sodium salt ora potassium salt.

The invention provides for a pharmaceutical composition according to theinvention, wherein the pharmaceutical composition comprises theantisense oligonucleotide progranulin agonist of the invention or theconjugate of the invention, or the pharmaceutically acceptable salt ofthe invention; and an aqueous diluent or solvent.

The invention provides for a solution, such as a phosphate bufferedsaline solution of the antisense oligonucleotide progranulin agonist ofthe invention, or the conjugate of the invention, or thepharmaceutically acceptable salt of the invention. Suitably thesolution, such as phosphate buffered saline solution, of the invention,is a sterile solution.

The invention provides for a method for enhancing the expression ofprogranulin in a cell which is expressing progranulin, said methodcomprising administering an antisense oligonucleotide progranulinagonist of the invention or the conjugate of the invention, or the saltaccording to the invention, or the pharmaceutical composition accordingto the invention in an effective amount to said cell. In someembodiments the method is an in vitro method. In some embodiments themethod is an in vivo method.

In some embodiments, the cell is either a human cell or a mammaliancell.

The invention provides for a method for treating or preventingneurological disease, comprising administering a therapeutically orprophylactically effective amount of an antisense oligonucleotideprogranulin agonist of the invention or the conjugate of the invention,or the salt of the invention, or the pharmaceutical composition of theinvention to a subject suffering from or susceptible to neurologicaldisease. In one embodiment the neurological disease may be a TDP-43pathology.

The invention provides for a method for treating progranulinhaploinsufficiency disease, comprising administering a therapeuticallyor prophylactically effective amount of an antisense oligonucleotideprogranulin agonist of the invention or the conjugate of the invention,or the salt of the invention, or the pharmaceutical composition of theinvention to a subject suffering from progranulin haploinsufficiency ora related disorder.

The invention provides for an antisense oligonucleotide progranulinagonist, for use as a medicament.

The invention provides for an antisense oligonucleotide progranulinagonist, for use in therapy.

The invention provides for the antisense oligonucleotide progranulinagonist of the invention or the conjugate of the invention, or the saltof the invention, or the pharmaceutical composition of the invention,for use as a medicament.

The invention provides an antisense oligonucleotide progranulin agonistof the invention or the conjugate of the invention, or the saltaccording to the invention, or the pharmaceutical composition accordingto the invention for use in therapy.

The invention provides for an antisense oligonucleotide progranulinagonist of the invention or the conjugate according to the invention, orthe salt according to the invention, or the pharmaceutical compositionaccording to the invention for use in the treatment of a neurologicaldisease. In one embodiment the neurological disease may be a TDP-43pathology.

The invention provides for an antisense oligonucleotide progranulinagonist of the invention or the conjugate according to the invention, orthe salt according to the invention, or the pharmaceutical compositionaccording to the invention for use in the treatment of progranulinhaploinsufficiency, or a related disorder.

The invention provides for the use of an antisense oligonucleotideprogranulin agonist of the invention or the conjugate according to theinvention, or the salt according to the invention, or the pharmaceuticalcomposition according to the invention, for the preparation of amedicament for treatment or prevention of a neurological disease In oneembodiment the neurological disease may be a TDP-43 pathology.

The invention provides for the use of the antisense oligonucleotideprogranulin agonist of the invention or the conjugate according to theinvention, or the salt according to the invention, or the pharmaceuticalcomposition according to the invention, for the preparation of amedicament for treatment of progranulin haploinsufficiency or a relateddisorder.

In some embodiments the method or use of the invention is for thetreatment of fronto temporal dementia (FTD), neuropathologicfrontotemporal lobar degeneration or neuroinflammation. In otherembodiments the method or use of the invention is for the treatment ofamyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson'sdisease, Autism, Hippocampal sclerosis dementia, Down syndrome,Huntington's disease, polyglutamine diseases, spinocerebellar ataxia 3,myopathies or Chronic Traumatic Encephalopathy.

In one aspect the invention includes an oligonucleotide progranulinagonist having the structure:

The invention also includes an antisense oligonucleotide progranulinagonist wherein the oligonucleotide is the oligonucleotide compoundTgGccAggGatCagGG (SEQ ID NO: 106) wherein capital letters representbeta-D-oxy LNA nucleosides, lowercase letters represent DNA nucleosides,all LNA C are 5-methyl cytosine, and all internucleoside linkages arephosphorothioate internucleoside linkages.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 shows progranulin expression levels in H4 neuroglioma cellsfollowing 5 days of treatment with 16-mer oligos targeting theprogranulin 5′ UTR uORF region. Progranulin expression levels wereevaluated in media after dilution 1:8 by ELISA from Abcam (ab252364).

FIG. 2 shows localization of compounds #105, #106, #110 and #114 to the5′ UTR of the proganulin mature mRNA transcript, targeting the uORFregion.

FIGS. 3 and 4 show progranulin expression levels in H4 neuroglioma cellsfollowing 5 days of treatment with 16-mer oligos targeting 5′ UTR uORFregion. Progranulin expression levels were evaluated in cell lysate(RIPA lysis and extraction buffer from Pierce cat. No. 89900) using theWES platform (ProteinSimple) and GRN antibody Invitrogen PA5-27275diluted 1:25 and HPRT1 antibody ab109021 (Abcam) diluted 1:50.

FIG. 5 shows the level of progranulin expression in hiPSC derivedmicoglia following 5 days of treatment with Compound #106. Progranulinexpression levels were evaluated in media after dilution 1:8 by ELISAfrom Abcam (ab252364).

FIG. 6 shows progranulin expression levels in H4 neuroglioma cellsfollowing 5 days of treatment with 18-mer oligos targeting theprogranulin 5′ UTR uORF region. Progranulin expression levels wereevaluated in media after dilution 1:8 by ELISA from Abcam (ab252364).

FIG. 7 shows the structure of Compound ID #106 (SEQ ID NO 106).

FIG. 8 shows progranulin expression in H4 neuroglioma cells followingtreatment with Compound #106, Compound #106 full 2′MOE, and Compound#106 full 2′oMe.

FIG. 9 shows heat maps indicating genes upregulated and down regulatedrelative to PBS control treated cells. Left is compound #106, middle isCompound #106 full 2′oMe and right is Compound #106 full 2′MOE.

FIG. 10 is a plot showing the position of oligos within the progranulinprecursor-mRNA (pre-mRNA) sequence (SEQ ID NO 3949) relative to theactivity of the oligo. Oligos complementary to exon-exon junctions areplotted downstream of the schematic figure of the pre-mRNA

DEFINITIONS

Progranulin Agonist

The term “progranulin agonist” as used herein refers to a compound whichis capable of enhancing the expression of progranulin transcripts and/orprotein in a cell which is expressing progranulin.

Tdp-43 Pathologies

A TDP-43 pathology is a disease which is associated with reduced oraberrant expression of TDP-43, often associated with an increase incytoplasmic TDP-43, particularly hyper-phosphorylated and ubiquitinatedTDP-43.

Diseases associated with TDP-43 pathology include amyotrophic lateralsclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer'sdisease, Parkinson's disease, Autism, Hippocampal sclerosis dementia,Down syndrome, Huntington's disease, polyglutamine diseases, such asspinocerebellar ataxia 3, myopathies and Chronic TraumaticEncephalopathy.

Oligonucleotide

The term “oligonucleotide” as used herein is defined as it is generallyunderstood by the skilled person as a molecule comprising two or morecovalently linked nucleosides. Such covalently bound nucleosides mayalso be referred to as nucleic acid molecules or oligomers.

Oligonucleotides are commonly made in the laboratory by solid-phasechemical synthesis followed by purification and isolation. Whenreferring to a sequence of the oligonucleotide, reference is made to thesequence or order of nucleobase moieties, or modifications thereof, ofthe covalently linked nucleotides or nucleosides. The oligonucleotidesof the invention are man-made, and are chemically synthesized, and aretypically purified or isolated. The oligonucleotides of the inventionmay comprise one or more modified nucleosides such as 2′ sugar modifiednucleosides. The oligonucleotides of the invention may comprise one ormore modified internucleoside linkages, such as one or morephosphorothioate internucleoside linkages.

Antisense Oligonucleotides

The term “antisense oligonucleotide” as used herein is defined as anoligonucleotide capable of modulating expression of a target gene byhybridizing to a target nucleic acid, in particular to a contiguoussequence on a target nucleic acid. Antisense oligonucleotides are notessentially double stranded and are therefore not siRNAs or shRNAs. Theantisense oligonucleotides of the present invention may be singlestranded. It is understood that single stranded oligonucleotides of thepresent invention can form hairpins or intermolecular duplex structures(duplex between two molecules of the same oligonucleotide), as long asthe degree of intra or inter self-complementarity is less thanapproximately 50% across of the full length of the oligonucleotide.

In some embodiments, the single stranded antisense oligonucleotides ofthe invention may not contain RNA nucleosides.

Advantageously, the antisense oligonucleotides of the invention compriseone or more modified nucleosides or nucleotides, such as 2′ sugarmodified nucleosides. Furthermore, in some antisense oligonucleotides ofthe invention, it may be advantageous that the nucleosides which are notmodified are DNA nucleosides.

Contiguous Nucleotide Sequence

The term “contiguous nucleotide sequence” refers to the region of theoligonucleotide which is complementary to a target nucleic acid, whichmay be or may comprise an oligonucleotide motif sequence. The term isused interchangeably herein with the term “contiguous nucleobasesequence”. In some embodiments all the nucleosides of theoligonucleotide constitute the contiguous nucleotide sequence. Thecontiguous nucleotide sequence is the sequence of nucleotides in theoligonucleotide of the invention which are complementary to, and in someinstances fully complementary to, the target nucleic acid or targetsequence, or target site sequence.

In some embodiments the target sequence is SEQ ID NO 2.

SEQ ID NO 2: TAGCCCTGATCCCTGGCCAATGGAAACTGAGGTAGG

In some embodiments the target sequence is selected from the groupconsisting of SEQ ID NO 343-682.

In some embodiments the target sequence is nucleotides 38-246 of SEQ IDNO 1.

In some embodiments the target sequence is selected from the groupconsisting of SEQ ID NO 568, SEQ ID NO 571, SEQ ID NO 575, SEQ ID NO576, SEQ ID NO 577, SEQ ID NO 578, SEQ ID NO 584 & SEQ ID NO 586.

In some embodiments the target sequence is SEQ ID NO 683.

SEQ ID NO 683 = TGGCCAATGGAAACTGAGGTAGG

In some embodiments the target sequence is SEQ ID NO 684.

SEQ ID NO 684 = CCCTAGCACCTCCCCCTAACCAAATTCTCCCTG

In some embodiments the target sequence is SEQ ID NO 685.

SEQ ID NO 685 = CCCATTCTGAGCTCCCCATCA

In some embodiments the target sequence is SEQ ID NO 686.

SEQ ID NO 686 = AGGGGGTTGTGGCAAAAGCCA

In some embodiments the target sequence is SEQ ID NO 687.

SEQ ID NO 687 = CCATCCCCTCCCCGTTTCAGT

In some embodiments the target sequence is SEQ ID NO 688.

SEQ ID NO 688 = ATCCACAGGGGTGTTTGT

In some embodiments the target sequence is SEQ ID NO 689.

SEQ ID NO 689 = TAAGTAGCCAATGGGAGCGGGTAGCCCTGATCCCTGGCCAATGGAAACTGAGGTAGG

SEQ ID NO 689 is in the human progranulin mature mRNA 5′ UTR fromposition 119 to 158 according to RefSeq NM_002087 (SEQ ID NO 1), astargeted by SEQ ID NOs 207 to 246 and identified herein as anadvantageous region to target for progranulin agonist activity.

In some embodiments the target sequence is nucleotides 2039-2346 of SEQID NO 1.

In some embodiments the target sequence is selected from the groupconsisting of SEQ ID NO 684, SEQ ID NO 685, SEQ ID NO 683, SEQ ID NO686, SEQ ID NO 687, and SEQ ID NO 688.

In some embodiments the target sequence is selected from the groupconsisting of SEQ ID NO 607, SEQ ID NO 608, SEQ ID NO 609, SEQ ID NO610, SEQ ID NO 611, SEQ ID NO 612, SEQ ID NO 619, SEQ ID NO 620, SEQ IDNO 633, SEQ ID NO 640, SEQ ID NO 641, SEQ ID NO 645, SEQ ID NO 651, andSEQ ID NO 652.

In some embodiments the target sequence is selected from the groupconsisting of SEQ ID NO 2040-3386.

In some embodiments the target sequence is selected from the groupconsisting of SEQ ID 2321, SEQ ID 2322, SEQ ID 2324, SEQ ID 2328, SEQ ID2329, SEQ ID 2331, SEQ ID 2334, SEQ ID 2335, SEQ ID 2336, SEQ ID 2337,SEQ ID 2338, SEQ ID 2339, SEQ ID 2340, SEQ ID 2341, SEQ ID 2342, SEQ ID2345, SEQ ID 2346, SEQ ID 2347, SEQ ID 2348, SEQ ID 2349, SEQ ID 2350,SEQ ID 2351, SEQ ID 2352, SEQ ID 2353, SEQ ID 2354, SEQ ID 2355, SEQ ID2356, SEQ ID 2357, SEQ ID 2358, SEQ ID 2359, SEQ ID 2360, SEQ ID 2361,SEQ ID 2362, SEQ ID 2364, SEQ ID 2365, SEQ ID 2366, SEQ ID 2367, SEQ ID2368, SEQ ID 2369, SEQ ID 2370, SEQ ID 2371, SEQ ID 2372, SEQ ID 2373,SEQ ID 2374, SEQ ID 2375, SEQ ID 2376, SEQ ID 2377, SEQ ID 2378, SEQ ID2379, SEQ ID 2380, SEQ ID 2381, SEQ ID 2384, SEQ ID 2386, SEQ ID 2387,SEQ ID 2388, SEQ ID 2389, SEQ ID 2390, SEQ ID 2392, SEQ ID 2393, SEQ ID2394, SEQ ID 2395, SEQ ID 2396, SEQ ID 2397, SEQ ID 2398, SEQ ID 2399,SEQ ID 2400, SEQ ID 2401, SEQ ID 2403, SEQ ID 2404, SEQ ID 2405, SEQ ID2406, SEQ ID 2407, SEQ ID 2408, SEQ ID 2410, SEQ ID 2411, SEQ ID 2413,SEQ ID 2414, SEQ ID 2415, SEQ ID 2416, SEQ ID 2418, SEQ ID 2419, SEQ ID2421, SEQ ID 2424, SEQ ID 2425, SEQ ID 2426, SEQ ID 2427, SEQ ID 2428,SEQ ID 2429, SEQ ID 2430, SEQ ID 2431, SEQ ID 2432, SEQ ID 2433, SEQ ID2434, SEQ ID 2435, SEQ ID 2436, SEQ ID 2437, SEQ ID 2438, SEQ ID 2439,SEQ ID 2440, SEQ ID 2441, SEQ ID 2442, SEQ ID 2443, SEQ ID 2444, SEQ ID2445, SEQ ID 2446, SEQ ID 2447, SEQ ID 2448, SEQ ID 2449, SEQ ID 2450,SEQ ID 2451, SEQ ID 2452, SEQ ID 2453, SEQ ID 2454, SEQ ID 2455, SEQ ID2456, SEQ ID 2457, SEQ ID 2458, SEQ ID 2459, SEQ ID 2460, SEQ ID 2461,SEQ ID 2462, SEQ ID 2463, SEQ ID 2464, SEQ ID 2465, SEQ ID 2466, SEQ ID2467, SEQ ID 2468, SEQ ID 2469, SEQ ID 2470, SEQ ID 2471, SEQ ID 2472,SEQ ID 2473, SEQ ID 2474, SEQ ID 2475, SEQ ID 2476, SEQ ID 2477, SEQ ID2478, SEQ ID 2479, SEQ ID 2481, SEQ ID 2482, SEQ ID 2483, SEQ ID 2484,SEQ ID 2485, SEQ ID 2487, SEQ ID 2489, SEQ ID 2490, SEQ ID 2491, SEQ ID2492, SEQ ID 2493, SEQ ID 2494, SEQ ID 2495, SEQ ID 2496, SEQ ID 2497,SEQ ID 2498, SEQ ID 2499, SEQ ID 2501, SEQ ID 2502, SEQ ID 2503, SEQ ID2504, SEQ ID 2505, SEQ ID 2506, SEQ ID 2507, SEQ ID 2508, SEQ ID 2509,SEQ ID 2510, SEQ ID 2511, SEQ ID 2512, SEQ ID 2513, SEQ ID 2514, SEQ ID2515, SEQ ID 2516, SEQ ID 2518, SEQ ID 2519, SEQ ID 2520, SEQ ID 2521,SEQ ID 2522, SEQ ID 2523, SEQ ID 2524, SEQ ID 2525, SEQ ID 2526, SEQ ID2527, SEQ ID 2528, SEQ ID 2531, SEQ ID 2533, SEQ ID 2534, SEQ ID 2535,SEQ ID 2536, SEQ ID 2537, SEQ ID 2538, SEQ ID 2540, SEQ ID 2541, SEQ ID2542, SEQ ID 2544, SEQ ID 2546, SEQ ID 2547, SEQ ID 2549, SEQ ID 2550,SEQ ID 2551, SEQ ID 2553, SEQ ID 2554, SEQ ID 2555, SEQ ID 2556, SEQ ID2557, SEQ ID 2560, SEQ ID 2561, SEQ ID 2562, SEQ ID 2563, SEQ ID 2565,SEQ ID 2566, SEQ ID 2567, SEQ ID 2572, SEQ ID 2573, SEQ ID 2574, SEQ ID2575, SEQ ID 2576, SEQ ID 2577, SEQ ID 2578, SEQ ID 2579, SEQ ID 2580,SEQ ID 2581, SEQ ID 2582, SEQ ID 2583, SEQ ID 2584, SEQ ID 2585, SEQ ID2586, SEQ ID 2588, SEQ ID 2589, SEQ ID 2590, SEQ ID 2591, SEQ ID 2592,SEQ ID 2593, SEQ ID 2594, SEQ ID 2595, SEQ ID 2596, SEQ ID 2597, SEQ ID2598, SEQ ID 2599, SEQ ID 2601, SEQ ID 2602, SEQ ID 2603, SEQ ID 2604,SEQ ID 2606, SEQ ID 2610, SEQ ID 2613, SEQ ID 2614, SEQ ID 2615, SEQ ID2619, SEQ ID 2622, SEQ ID 2623, SEQ ID 2624, SEQ ID 2625, SEQ ID 2626,SEQ ID 2627, SEQ ID 2628, SEQ ID 2629, SEQ ID 2630, SEQ ID 2631, SEQ ID2632, SEQ ID 2633, SEQ ID 2634, SEQ ID 2635, SEQ ID 2636, SEQ ID 2637,SEQ ID 2638, SEQ ID 2639, SEQ ID 2640, SEQ ID 2641, SEQ ID 2642, SEQ ID2643, SEQ ID 2644, SEQ ID 2645, SEQ ID 2646, SEQ ID 2647, SEQ ID 2648,SEQ ID 2649, SEQ ID 2650, SEQ ID 2651, SEQ ID 2652, SEQ ID 2653, SEQ ID2654, SEQ ID 2655, SEQ ID 2656, SEQ ID 2658, SEQ ID 2659, SEQ ID 2660,SEQ ID 2661, SEQ ID 2662, SEQ ID 2663, SEQ ID 2664, SEQ ID 2665, SEQ ID2666, SEQ ID 2667, SEQ ID 2668, SEQ ID 2669, SEQ ID 2670, SEQ ID 2671,SEQ ID 2672, SEQ ID 2673, SEQ ID 2674, SEQ ID 2675, SEQ ID 2676, SEQ ID2677, SEQ ID 2678, SEQ ID 2679, SEQ ID 2680, SEQ ID 2681, SEQ ID 2682,SEQ ID 2683, SEQ ID 2684, SEQ ID 2685, SEQ ID 2686, SEQ ID 2687, SEQ ID2688, SEQ ID 2689, SEQ ID 2690, SEQ ID 2691, SEQ ID 2693, SEQ ID 2694,SEQ ID 2695, SEQ ID 2696, SEQ ID 2697, SEQ ID 2698, SEQ ID 2699, SEQ ID2700, SEQ ID 2701, SEQ ID 2702, SEQ ID 2703, SEQ ID 2704, SEQ ID 2705,SEQ ID 2706, SEQ ID 2707, SEQ ID 2708, SEQ ID 2709, SEQ ID 2710, SEQ ID2711, SEQ ID 2712, SEQ ID 2713, SEQ ID 2714, SEQ ID 2715, SEQ ID 2716,SEQ ID 2717, SEQ ID 2718, SEQ ID 2719, SEQ ID 2720, SEQ ID 2721, SEQ ID2722, SEQ ID 2723, SEQ ID 2726, SEQ ID 2727, SEQ ID 2728, SEQ ID 2729,SEQ ID 2730, SEQ ID 2733, SEQ ID 2734, SEQ ID 2735, SEQ ID 2736, SEQ ID2737, SEQ ID 2738, SEQ ID 2739, SEQ ID 2740, SEQ ID 2741, SEQ ID 2742,SEQ ID 2743, SEQ ID 2744, SEQ ID 2745, SEQ ID 2746, SEQ ID 2747, SEQ ID2748, SEQ ID 2749, SEQ ID 2750, SEQ ID 2751, SEQ ID 2752, SEQ ID 2753,SEQ ID 2754, SEQ ID 2755, SEQ ID 2756, SEQ ID 2757, SEQ ID 2758, SEQ ID2759, SEQ ID 2760, SEQ ID 2761, SEQ ID 2762, SEQ ID 2763, SEQ ID 2764,SEQ ID 2765, SEQ ID 2766, SEQ ID 2767, SEQ ID 2768, SEQ ID 2769, SEQ ID2770, SEQ ID 2771, SEQ ID 2772, SEQ ID 2773, SEQ ID 2774, SEQ ID 2775,SEQ ID 2815, SEQ ID 2816, SEQ ID 2817, SEQ ID 2818, SEQ ID 2819, SEQ ID2820, SEQ ID 2821, SEQ ID 2822, SEQ ID 2823, SEQ ID 2824, SEQ ID 2825,SEQ ID 2826, SEQ ID 2827, SEQ ID 2828, SEQ ID 2829, SEQ ID 2830, SEQ ID2831, SEQ ID 2832, SEQ ID 2833, SEQ ID 2834, SEQ ID 2835, SEQ ID 2836,SEQ ID 2837, SEQ ID 2838, SEQ ID 2839, SEQ ID 2840, SEQ ID 2841, SEQ ID2842, SEQ ID 2843, SEQ ID 2844, SEQ ID 2845, SEQ ID 2847, SEQ ID 2848,SEQ ID 2849, SEQ ID 2850, SEQ ID 2851, SEQ ID 2852, SEQ ID 2853, SEQ ID2854, SEQ ID 2855, SEQ ID 2858, SEQ ID 2859, SEQ ID 2860, SEQ ID 2861,SEQ ID 2862, SEQ ID 2863, SEQ ID 2864, SEQ ID 2865, SEQ ID 2866, SEQ ID2867, SEQ ID 2868, SEQ ID 2869, SEQ ID 2870, SEQ ID 2871, SEQ ID 2872,SEQ ID 2873, SEQ ID 2874, SEQ ID 2875, SEQ ID 2876, SEQ ID 2878, SEQ ID2879, SEQ ID 2880, SEQ ID 2881, SEQ ID 2882, SEQ ID 2883, SEQ ID 2884,SEQ ID 2885, SEQ ID 2886, SEQ ID 2887, SEQ ID 2888, SEQ ID 2889, SEQ ID2890, SEQ ID 2891, SEQ ID 2892, SEQ ID 2893, SEQ ID 2894, SEQ ID 2895,SEQ ID 2896, SEQ ID 2897, SEQ ID 2898, SEQ ID 2899, SEQ ID 2900, SEQ ID2901, SEQ ID 2902, SEQ ID 2903, SEQ ID 2904, SEQ ID 2905, SEQ ID 2906,SEQ ID 2907, SEQ ID 2908, SEQ ID 2909, SEQ ID 2910, SEQ ID 2911, SEQ ID2912, SEQ ID 2913, SEQ ID 2914, SEQ ID 2915, SEQ ID 2916, SEQ ID 2917,SEQ ID 2918, SEQ ID 2919, SEQ ID 2920, SEQ ID 2921, SEQ ID 2922, SEQ ID2923, SEQ ID 2924, SEQ ID 2925, SEQ ID 2926, SEQ ID 2927, SEQ ID 2928,SEQ ID 2929, SEQ ID 2930, SEQ ID 2931, SEQ ID 2932, SEQ ID 2934, SEQ ID2935, SEQ ID 2936, SEQ ID 2937, SEQ ID 2938, SEQ ID 2939, SEQ ID 2940,SEQ ID 2941, SEQ ID 2942, SEQ ID 2943, SEQ ID 2944, SEQ ID 2945, SEQ ID2946, SEQ ID 2947, SEQ ID 2948, SEQ ID 2949, SEQ ID 2950, SEQ ID 2951,SEQ ID 2953, SEQ ID 2954, SEQ ID 2955, SEQ ID 2956, SEQ ID 2957, SEQ ID2958, SEQ ID 2960, SEQ ID 2961, SEQ ID 2963, SEQ ID 2964, SEQ ID 2965,SEQ ID 2966, SEQ ID 2967, SEQ ID 2969, SEQ ID 2970, SEQ ID 2971, SEQ ID2972, SEQ ID 2973, SEQ ID 2974, SEQ ID 2975, SEQ ID 2976, SEQ ID 2977,SEQ ID 2978, SEQ ID 2979, SEQ ID 2980, SEQ ID 2981, SEQ ID 2982, SEQ ID2983, SEQ ID 2984, SEQ ID 2985, SEQ ID 3053, SEQ ID 3054, SEQ ID 3055,SEQ ID 3056, SEQ ID 3057, SEQ ID 3058, SEQ ID 3059, SEQ ID 3060, SEQ ID3061, SEQ ID 3062, SEQ ID 3063, SEQ ID 3064, SEQ ID 3065, SEQ ID 3066,SEQ ID 3068, SEQ ID 3069, SEQ ID 3070, SEQ ID 3071, SEQ ID 3072, SEQ ID3073, SEQ ID 3074, SEQ ID 3075, SEQ ID 3076, SEQ ID 3077, SEQ ID 3078,SEQ ID 3079, SEQ ID 3080, SEQ ID 3081, SEQ ID 3082, SEQ ID 3083, SEQ ID3084, SEQ ID 3085, SEQ ID 3086, SEQ ID 3087, SEQ ID 3088, SEQ ID 3089,SEQ ID 3090, SEQ ID 3091, SEQ ID 3092, SEQ ID 3093, SEQ ID 3094, SEQ ID3095, SEQ ID 3097, SEQ ID 3098, SEQ ID 3099, SEQ ID 3100, SEQ ID 3102,SEQ ID 3103, SEQ ID 3104, SEQ ID 3105, SEQ ID 3106, SEQ ID 3107, SEQ ID3108, SEQ ID 3109, SEQ ID 3110, SEQ ID 3112, SEQ ID 3113, SEQ ID 3115,SEQ ID 3116, SEQ ID 3117, SEQ ID 3119, SEQ ID 3120, SEQ ID 3121, SEQ ID3122, SEQ ID 3123, SEQ ID 3124, SEQ ID 3125, SEQ ID 3126, SEQ ID 3127,SEQ ID 3128, SEQ ID 3129, SEQ ID 3130, SEQ ID 3131, SEQ ID 3132, SEQ ID3133, SEQ ID 3134, SEQ ID 3135, SEQ ID 3136, SEQ ID 3137, SEQ ID 3138,SEQ ID 3139, SEQ ID 3140, SEQ ID 3141, SEQ ID 3142, SEQ ID 3143, SEQ ID3144, SEQ ID 3145, SEQ ID 3146, SEQ ID 3147, SEQ ID 3148, SEQ ID 3149,SEQ ID 3150, SEQ ID 3151, SEQ ID 3152, SEQ ID 3153, SEQ ID 3154, SEQ ID3155, SEQ ID 3156, SEQ ID 3157, SEQ ID 3158, SEQ ID 3159, SEQ ID 3160,SEQ ID 3161, SEQ ID 3162, SEQ ID 3163, SEQ ID 3164, SEQ ID 3165, SEQ ID3166, SEQ ID 3167, SEQ ID 3168, SEQ ID 3169, SEQ ID 3170, SEQ ID 3171,SEQ ID 3172, SEQ ID 3173, SEQ ID 3174, SEQ ID 3175, SEQ ID 3176, SEQ ID3177, SEQ ID 3178, SEQ ID 3179, SEQ ID 3180, SEQ ID 3181, SEQ ID 3182,SEQ ID 3183, SEQ ID 3184, SEQ ID 3185, SEQ ID 3186, SEQ ID 3187, SEQ ID3188, SEQ ID 3189, SEQ ID 3190, SEQ ID 3191, SEQ ID 3192, SEQ ID 3193,SEQ ID 3194, SEQ ID 3195, SEQ ID 3196, SEQ ID 3197, SEQ ID 3198, SEQ ID3199, SEQ ID 3200, SEQ ID 3201, SEQ ID 3202, SEQ ID 3203, SEQ ID 3204,SEQ ID 3205, SEQ ID 3206, SEQ ID 3207, SEQ ID 3208, SEQ ID 3209, SEQ ID3210, SEQ ID 3211, SEQ ID 3212, SEQ ID 3213, SEQ ID 3214, SEQ ID 3215,SEQ ID 3216, SEQ ID 3217, SEQ ID 3218, SEQ ID 3219, SEQ ID 3220, SEQ ID3221, SEQ ID 3222, SEQ ID 3223, SEQ ID 3224, SEQ ID 3225, SEQ ID 3226,SEQ ID 3227, SEQ ID 3228, SEQ ID 3229, SEQ ID 3230, SEQ ID 3231, SEQ ID3232, SEQ ID 3233, SEQ ID 3234, SEQ ID 3235, SEQ ID 3236, SEQ ID 3237,SEQ ID 3238, SEQ ID 3239, SEQ ID 3240, SEQ ID 3241, SEQ ID 3242, SEQ ID3243, SEQ ID 3244, SEQ ID 3245, SEQ ID 3246, SEQ ID 3248, SEQ ID 3249,SEQ ID 3250, SEQ ID 3251, SEQ ID 3252, SEQ ID 3253, SEQ ID 3254, SEQ ID3255, SEQ ID 3256, SEQ ID 3257, SEQ ID 3258, SEQ ID 3259, SEQ ID 3260,SEQ ID 3261, SEQ ID 3262, SEQ ID 3263, SEQ ID 3264, SEQ ID 3265, SEQ ID3266, SEQ ID 3267, SEQ ID 3268, SEQ ID 3269, SEQ ID 3270, SEQ ID 3271,SEQ ID 3272, SEQ ID 3273, SEQ ID 3275, SEQ ID 3276, SEQ ID 3277, SEQ ID3278, SEQ ID 3279, SEQ ID 3280, SEQ ID 3282, SEQ ID 3284, SEQ ID 3285,SEQ ID 3286, SEQ ID 3287, SEQ ID 3288, SEQ ID 3289, SEQ ID 3291, SEQ ID3292, SEQ ID 3293, SEQ ID 3294, SEQ ID 3295, SEQ ID 3296, SEQ ID 3297,SEQ ID 3298, SEQ ID 3299, SEQ ID 3300, SEQ ID 3301, SEQ ID 3302, SEQ ID3303, SEQ ID 3304, SEQ ID 3305, SEQ ID 3306, SEQ ID 3307, SEQ ID 3308,SEQ ID 3309, SEQ ID 3310, SEQ ID 3311, SEQ ID 3312, SEQ ID 3313, SEQ ID3314, SEQ ID 3315, SEQ ID 3316, SEQ ID 3317, SEQ ID 3318, SEQ ID 3320,SEQ ID 3321, SEQ ID 3322, SEQ ID 3323, SEQ ID 3324, SEQ ID 3325, SEQ ID3326, SEQ ID 3327, SEQ ID 3329, SEQ ID 3331, SEQ ID 3332, SEQ ID 3333,SEQ ID 3334, SEQ ID 3335, SEQ ID 3336, SEQ ID 3337, SEQ ID 3338, SEQ ID3339, SEQ ID 3340, SEQ ID 3342, SEQ ID 3343, SEQ ID 3344, SEQ ID 3345,SEQ ID 3346, SEQ ID 3347, SEQ ID 3348, SEQ ID 3349, SEQ ID 3350, SEQ ID3351, SEQ ID 3352, SEQ ID 3353, SEQ ID 3354, SEQ ID 3355, SEQ ID 3356,SEQ ID 3357, SEQ ID 3358, SEQ ID 3359, SEQ ID 3360, SEQ ID 3361, SEQ ID3362, SEQ ID 3363, SEQ ID 3364, SEQ ID 3365, SEQ ID 3366, SEQ ID 3367,SEQ ID 3368, SEQ ID 3369, SEQ ID 3370, SEQ ID 3371, SEQ ID 3390, SEQ ID3391, SEQ ID 3392, SEQ ID 3393, SEQ ID 3394, SEQ ID 3395, SEQ ID 3396,SEQ ID 3397, SEQ ID 3398, SEQ ID 3399, SEQ ID 3400, SEQ ID 3401, SEQ ID3402, SEQ ID 3403, SEQ ID 3404, SEQ ID 3405, SEQ ID 3406, SEQ ID 3407,SEQ ID 3408, SEQ ID 3409, SEQ ID 3410, SEQ ID 3411, SEQ ID 3412, SEQ ID3413, SEQ ID 3414, SEQ ID 3415, SEQ ID 3416, SEQ ID 3417, SEQ ID 3418,SEQ ID 3419, SEQ ID 3420, SEQ ID 3421, SEQ ID 3422, SEQ ID 3423, SEQ ID3424, SEQ ID 3425, SEQ ID 3426, SEQ ID 3427, SEQ ID 3428, SEQ ID 3429,SEQ ID 3430, SEQ ID 3431, SEQ ID 3432, SEQ ID 3433, SEQ ID 3434, SEQ ID3435, SEQ ID 3436, SEQ ID 3437, SEQ ID 3438, SEQ ID 3439, SEQ ID 3440,SEQ ID 3441, SEQ ID 3442, SEQ ID 3443, SEQ ID 3444, SEQ ID 3445, SEQ ID3446, SEQ ID 3447, SEQ ID 3448, SEQ ID 3449, SEQ ID 3450, SEQ ID 3451,SEQ ID 3452, SEQ ID 3453, SEQ ID 3454, SEQ ID 3460, SEQ ID 3461, SEQ ID3464, SEQ ID 3465, SEQ ID 3466, SEQ ID 3467, SEQ ID 3468, SEQ ID 3486,SEQ ID 3487, SEQ ID 3488, SEQ ID 3489, SEQ ID 3490, SEQ ID 3491, SEQ ID3493, SEQ ID 3494, SEQ ID 3496, SEQ ID 3497, SEQ ID 3501, SEQ ID 3505,SEQ ID 3508, SEQ ID 3511, SEQ ID 3512, SEQ ID 3516, SEQ ID 3517, SEQ ID3518, SEQ ID 3521, SEQ ID 3522, SEQ ID 3523, SEQ ID 3524, SEQ ID 3525,SEQ ID 3526, SEQ ID 3527, SEQ ID 3528, SEQ ID 3530, SEQ ID 3531, SEQ ID3532, SEQ ID 3534, SEQ ID 3535, SEQ ID 3536, SEQ ID 3538, SEQ ID 3539,SEQ ID 3541, SEQ ID 3542, SEQ ID 3543, SEQ ID 3544, SEQ ID 3546, SEQ ID3548, SEQ ID 3549, SEQ ID 3550, SEQ ID 3552, SEQ ID 3556, SEQ ID 3557,SEQ ID 3558, SEQ ID 3560, SEQ ID 3561, SEQ ID 3566, SEQ ID 3567, SEQ ID3568, SEQ ID 3569, SEQ ID 3571, SEQ ID 3572, SEQ ID 3573, SEQ ID 3574,SEQ ID 3576, SEQ ID 3577, SEQ ID 3578, SEQ ID 3580, SEQ ID 3581, SEQ ID3584, SEQ ID 3585, SEQ ID 3586, SEQ ID 3588, SEQ ID 3590, SEQ ID 3592,SEQ ID 3594, SEQ ID 3595, SEQ ID 3598, SEQ ID 3599, SEQ ID 3600, SEQ ID3601, SEQ ID 3602, SEQ ID 3603, SEQ ID 3605, SEQ ID 3607, SEQ ID 3609,SEQ ID 3610, SEQ ID 3613, SEQ ID 3614, SEQ ID 3615, SEQ ID 3616, SEQ ID3617, SEQ ID 3621, SEQ ID 3623, SEQ ID 3624, SEQ ID 3625, SEQ ID 3626,SEQ ID 3627, SEQ ID 3628, SEQ ID 3629, SEQ ID 3630, SEQ ID 3631, SEQ ID3632, SEQ ID 3633, SEQ ID 3636, SEQ ID 3637, SEQ ID 3638, SEQ ID 3639,SEQ ID 3641, SEQ ID 3642, SEQ ID 3643, SEQ ID 3645, SEQ ID 3647, SEQ ID3648, SEQ ID 3649, SEQ ID 3651, SEQ ID 3654, SEQ ID 3656, SEQ ID 3659,SEQ ID 3660, SEQ ID 3661, SEQ ID 3663, SEQ ID 3664, SEQ ID 3665, SEQ ID3666, SEQ ID 3670, SEQ ID 3672, SEQ ID 3676, SEQ ID 3678, SEQ ID 3679,SEQ ID 3680, SEQ ID 3681, SEQ ID 3682, SEQ ID 3683, SEQ ID 3684, SEQ ID3685, SEQ ID 3686, SEQ ID 3687, SEQ ID 3688, SEQ ID 3689, SEQ ID 3690,SEQ ID 3691, SEQ ID 3692, SEQ ID 3693, SEQ ID 3694, SEQ ID 3695, SEQ ID3696, SEQ ID 3697, SEQ ID 3698, SEQ ID 3699, SEQ ID 3700, SEQ ID 3701,SEQ ID 3702, SEQ ID 3703, SEQ ID 3704, SEQ ID 3705, SEQ ID 3706, SEQ ID3707, SEQ ID 3708, SEQ ID 3709, SEQ ID 3710, SEQ ID 3711, SEQ ID 3712,SEQ ID 3713, SEQ ID 3714, SEQ ID 3715, SEQ ID 3716, SEQ ID 3717, SEQ ID3718, SEQ ID 3719, SEQ ID 3720, SEQ ID 3721, SEQ ID 3722, SEQ ID 3723,SEQ ID 3724, SEQ ID 3725, SEQ ID 3726, SEQ ID 3727, SEQ ID 3729, SEQ ID3730, SEQ ID 3731, SEQ ID 3732, SEQ ID 3733, SEQ ID 3734, SEQ ID 3735,SEQ ID 3736, SEQ ID 3737, SEQ ID 3738, SEQ ID 3739, SEQ ID 3740, SEQ ID3741, SEQ ID 3742, SEQ ID 3743, SEQ ID 3744, SEQ ID 3745, SEQ ID 3746,SEQ ID 3747, SEQ ID 3748, SEQ ID 3749, SEQ ID 3750, SEQ ID 3751, SEQ ID3752, SEQ ID 3753, SEQ ID 3754, SEQ ID 3755, SEQ ID 3774, SEQ ID 3775,SEQ ID 3776, SEQ ID 3777, SEQ ID 3778, SEQ ID 3779, SEQ ID 3780, SEQ ID3781, SEQ ID 3782, SEQ ID 3783, SEQ ID 3784, SEQ ID 3785, SEQ ID 3786,SEQ ID 3787, SEQ ID 3788, SEQ ID 3789, SEQ ID 3790, SEQ ID 3791, SEQ ID3792, SEQ ID 3793, SEQ ID 3794, SEQ ID 3795, SEQ ID 3796, SEQ ID 3797,SEQ ID 3798, SEQ ID 3799, SEQ ID 3800, SEQ ID 3801, SEQ ID 3802, SEQ ID3803, SEQ ID 3804, SEQ ID 3805, SEQ ID 3806, SEQ ID 3807, SEQ ID 3808,SEQ ID 3809, SEQ ID 3810, SEQ ID 3811, SEQ ID 3812, SEQ ID 3813, SEQ ID3814, SEQ ID 3815, SEQ ID 3816, SEQ ID 3817, SEQ ID 3818, SEQ ID 3819,SEQ ID 3820, SEQ ID 3821, SEQ ID 3822, SEQ ID 3823, SEQ ID 3824, SEQ ID3825, SEQ ID 3826, SEQ ID 3827, SEQ ID 3828, SEQ ID 3829, SEQ ID 3830,SEQ ID 3831, SEQ ID 3832, SEQ ID 3833, SEQ ID 3834, SEQ ID 3835, SEQ ID3836, SEQ ID 3837, SEQ ID 3838, SEQ ID 3839, SEQ ID 3840, SEQ ID 3841,SEQ ID 3842, SEQ ID 3844, SEQ ID 3848, SEQ ID 3850, SEQ ID 3851, SEQ ID3852, SEQ ID 3853, SEQ ID 3867, SEQ ID 3868, SEQ ID 3869, SEQ ID 3870,SEQ ID 3871, SEQ ID 3872, SEQ ID 3873, SEQ ID 3874, SEQ ID 3875, SEQ ID3876, SEQ ID 3877, SEQ ID 3878, SEQ ID 3879, SEQ ID 3880, SEQ ID 3881,SEQ ID 3882, SEQ ID 3883, SEQ ID 3884, SEQ ID 3885, SEQ ID 3886, SEQ ID3887, SEQ ID 3888, SEQ ID 3889, SEQ ID 3890, SEQ ID 3891, SEQ ID 3892,SEQ ID 3893, SEQ ID 3894, SEQ ID 3895, SEQ ID 3896, SEQ ID 3897, SEQ ID3898, SEQ ID 3899, SEQ ID 3900, SEQ ID 3901, SEQ ID 3902, SEQ ID 3903,SEQ ID 3904, SEQ ID 3905, SEQ ID 3906, SEQ ID 3907, SEQ ID 3908, SEQ ID3909, SEQ ID 3910, SEQ ID 3911, SEQ ID 3912, SEQ ID 3913, SEQ ID 3914,SEQ ID 3915, SEQ ID 3916, SEQ ID 3917, SEQ ID 3918, SEQ ID 3919, SEQ ID3920, SEQ ID 3921, SEQ ID 3922, SEQ ID 3923, SEQ ID 3924, SEQ ID 3925,SEQ ID 3926, SEQ ID 3927, SEQ ID 3928, SEQ ID 3929, SEQ ID 3930, SEQ ID3931, SEQ ID 3932, SEQ ID 3933, SEQ ID 3934, SEQ ID 3935, SEQ ID 3936,SEQ ID 3937, SEQ ID 3938, SEQ ID 3939, SEQ ID 3940, SEQ ID 3941, SEQ ID3942, SEQ ID 3943, SEQ ID 3944, SEQ ID 3945, SEQ ID 3946, SEQ ID 3947,and SEQ ID 3948.

In some embodiments the target sequence is selected from the groupconsisting of SEQ ID 2321, SEQ ID 2335, SEQ ID 2336, SEQ ID 2337, SEQ ID2338, SEQ ID 2339, SEQ ID 2348, SEQ ID 2349, SEQ ID 2351, SEQ ID 2352,SEQ ID 2353, SEQ ID 2354, SEQ ID 2355, SEQ ID 2358, SEQ ID 2360, SEQ ID2364, SEQ ID 2365, SEQ ID 2366, SEQ ID 2367, SEQ ID 2369, SEQ ID 2371,SEQ ID 2373, SEQ ID 2375, SEQ ID 2386, SEQ ID 2387, SEQ ID 2388, SEQ ID2389, SEQ ID 2394, SEQ ID 2403, SEQ ID 2426, SEQ ID 2428, SEQ ID 2429,SEQ ID 2430, SEQ ID 2431, SEQ ID 2432, SEQ ID 2435, SEQ ID 2440, SEQ ID2441, SEQ ID 2442, SEQ ID 2444, SEQ ID 2446, SEQ ID 2447, SEQ ID 2450,SEQ ID 2451, SEQ ID 2452, SEQ ID 2453, SEQ ID 2454, SEQ ID 2455, SEQ ID2456, SEQ ID 2458, SEQ ID 2459, SEQ ID 2461, SEQ ID 2463, SEQ ID 2464,SEQ ID 2465, SEQ ID 2466, SEQ ID 2467, SEQ ID 2468, SEQ ID 2469, SEQ ID2470, SEQ ID 2471, SEQ ID 2472, SEQ ID 2473, SEQ ID 2474, SEQ ID 2475,SEQ ID 2476, SEQ ID 2477, SEQ ID 2478, SEQ ID 2482, SEQ ID 2483, SEQ ID2484, SEQ ID 2485, SEQ ID 2487, SEQ ID 2489, SEQ ID 2494, SEQ ID 2495,SEQ ID 2496, SEQ ID 2497, SEQ ID 2499, SEQ ID 2501, SEQ ID 2502, SEQ ID2504, SEQ ID 2506, SEQ ID 2507, SEQ ID 2508, SEQ ID 2509, SEQ ID 2511,SEQ ID 2513, SEQ ID 2515, SEQ ID 2516, SEQ ID 2518, SEQ ID 2519, SEQ ID2520, SEQ ID 2521, SEQ ID 2523, SEQ ID 2525, SEQ ID 2534, SEQ ID 2537,SEQ ID 2544, SEQ ID 2546, SEQ ID 2554, SEQ ID 2555, SEQ ID 2556, SEQ ID2560, SEQ ID 2561, SEQ ID 2562, SEQ ID 2595, SEQ ID 2626, SEQ ID 2628,SEQ ID 2629, SEQ ID 2630, SEQ ID 2631, SEQ ID 2633, SEQ ID 2638, SEQ ID2639, SEQ ID 2640, SEQ ID 2649, SEQ ID 2651, SEQ ID 2652, SEQ ID 2655,SEQ ID 2658, SEQ ID 2665, SEQ ID 2666, SEQ ID 2667, SEQ ID 2669, SEQ ID2670, SEQ ID 2676, SEQ ID 2677, SEQ ID 2678, SEQ ID 2679, SEQ ID 2682,SEQ ID 2686, SEQ ID 2688, SEQ ID 2689, SEQ ID 2691, SEQ ID 2694, SEQ ID2698, SEQ ID 2699, SEQ ID 2700, SEQ ID 2701, SEQ ID 2703, SEQ ID 2706,SEQ ID 2709, SEQ ID 2711, SEQ ID 2712, SEQ ID 2713, SEQ ID 2714, SEQ ID2719, SEQ ID 2720, SEQ ID 2721, SEQ ID 2737, SEQ ID 2739, SEQ ID 2740,SEQ ID 2741, SEQ ID 2742, SEQ ID 2743, SEQ ID 2744, SEQ ID 2745, SEQ ID2746, SEQ ID 2747, SEQ ID 2748, SEQ ID 2749, SEQ ID 2750, SEQ ID 2751,SEQ ID 2752, SEQ ID 2753, SEQ ID 2754, SEQ ID 2755, SEQ ID 2756, SEQ ID2757, SEQ ID 2758, SEQ ID 2760, SEQ ID 2763, SEQ ID 2764, SEQ ID 2765,SEQ ID 2766, SEQ ID 2767, SEQ ID 2768, SEQ ID 2769, SEQ ID 2770, SEQ ID2771, SEQ ID 2772, SEQ ID 2774, SEQ ID 2816, SEQ ID 2817, SEQ ID 2818,SEQ ID 2819, SEQ ID 2820, SEQ ID 2824, SEQ ID 2828, SEQ ID 2829, SEQ ID2830, SEQ ID 2831, SEQ ID 2832, SEQ ID 2833, SEQ ID 2834, SEQ ID 2835,SEQ ID 2836, SEQ ID 2837, SEQ ID 2851, SEQ ID 2852, SEQ ID 2866, SEQ ID2871, SEQ ID 2872, SEQ ID 2886, SEQ ID 2887, SEQ ID 2890, SEQ ID 2891,SEQ ID 2892, SEQ ID 2895, SEQ ID 2896, SEQ ID 2899, SEQ ID 2904, SEQ ID2910, SEQ ID 2911, SEQ ID 2912, SEQ ID 2913, SEQ ID 2914, SEQ ID 2916,SEQ ID 2918, SEQ ID 2919, SEQ ID 2920, SEQ ID 2922, SEQ ID 2925, SEQ ID2926, SEQ ID 2932, SEQ ID 2939, SEQ ID 2941, SEQ ID 2942, SEQ ID 2943,SEQ ID 2972, SEQ ID 2973, SEQ ID 2974, SEQ ID 2975, SEQ ID 2976, SEQ ID2977, SEQ ID 2980, SEQ ID 2983, SEQ ID 2985, SEQ ID 3053, SEQ ID 3054,SEQ ID 3055, SEQ ID 3056, SEQ ID 3058, SEQ ID 3059, SEQ ID 3060, SEQ ID3061, SEQ ID 3062, SEQ ID 3063, SEQ ID 3064, SEQ ID 3065, SEQ ID 3066,SEQ ID 3068, SEQ ID 3069, SEQ ID 3070, SEQ ID 3071, SEQ ID 3072, SEQ ID3073, SEQ ID 3074, SEQ ID 3075, SEQ ID 3076, SEQ ID 3077, SEQ ID 3078,SEQ ID 3079, SEQ ID 3082, SEQ ID 3083, SEQ ID 3084, SEQ ID 3085, SEQ ID3088, SEQ ID 3089, SEQ ID 3090, SEQ ID 3091, SEQ ID 3092, SEQ ID 3095,SEQ ID 3097, SEQ ID 3102, SEQ ID 3106, SEQ ID 3108, SEQ ID 3110, SEQ ID3116, SEQ ID 3120, SEQ ID 3121, SEQ ID 3125, SEQ ID 3126, SEQ ID 3133,SEQ ID 3134, SEQ ID 3135, SEQ ID 3137, SEQ ID 3138, SEQ ID 3140, SEQ ID3141, SEQ ID 3142, SEQ ID 3143, SEQ ID 3145, SEQ ID 3148, SEQ ID 3152,SEQ ID 3153, SEQ ID 3156, SEQ ID 3157, SEQ ID 3158, SEQ ID 3159, SEQ ID3160, SEQ ID 3161, SEQ ID 3162, SEQ ID 3163, SEQ ID 3164, SEQ ID 3165,SEQ ID 3166, SEQ ID 3167, SEQ ID 3168, SEQ ID 3169, SEQ ID 3170, SEQ ID3172, SEQ ID 3173, SEQ ID 3174, SEQ ID 3175, SEQ ID 3176, SEQ ID 3177,SEQ ID 3178, SEQ ID 3179, SEQ ID 3180, SEQ ID 3181, SEQ ID 3182, SEQ ID3183, SEQ ID 3184, SEQ ID 3186, SEQ ID 3188, SEQ ID 3191, SEQ ID 3193,SEQ ID 3196, SEQ ID 3197, SEQ ID 3203, SEQ ID 3205, SEQ ID 3206, SEQ ID3207, SEQ ID 3210, SEQ ID 3211, SEQ ID 3212, SEQ ID 3213, SEQ ID 3214,SEQ ID 3215, SEQ ID 3216, SEQ ID 3217, SEQ ID 3218, SEQ ID 3219, SEQ ID3221, SEQ ID 3222, SEQ ID 3223, SEQ ID 3224, SEQ ID 3227, SEQ ID 3236,SEQ ID 3237, SEQ ID 3238, SEQ ID 3239, SEQ ID 3240, SEQ ID 3241, SEQ ID3242, SEQ ID 3243, SEQ ID 3244, SEQ ID 3245, SEQ ID 3246, SEQ ID 3248,SEQ ID 3249, SEQ ID 3250, SEQ ID 3251, SEQ ID 3252, SEQ ID 3254, SEQ ID3258, SEQ ID 3259, SEQ ID 3261, SEQ ID 3263, SEQ ID 3265, SEQ ID 3266,SEQ ID 3267, SEQ ID 3271, SEQ ID 3272, SEQ ID 3273, SEQ ID 3276, SEQ ID3277, SEQ ID 3279, SEQ ID 3286, SEQ ID 3295, SEQ ID 3297, SEQ ID 3305,SEQ ID 3307, SEQ ID 3309, SEQ ID 3312, SEQ ID 3313, SEQ ID 3314, SEQ ID3316, SEQ ID 3317, SEQ ID 3318, SEQ ID 3320, SEQ ID 3332, SEQ ID 3335,SEQ ID 3336, SEQ ID 3337, SEQ ID 3338, SEQ ID 3339, SEQ ID 3340, SEQ ID3342, SEQ ID 3343, SEQ ID 3345, SEQ ID 3346, SEQ ID 3347, SEQ ID 3348,SEQ ID 3349, SEQ ID 3350, SEQ ID 3351, SEQ ID 3352, SEQ ID 3353, SEQ ID3354, SEQ ID 3355, SEQ ID 3356, SEQ ID 3359, SEQ ID 3360, SEQ ID 3361,SEQ ID 3362, SEQ ID 3363, SEQ ID 3364, SEQ ID 3365, SEQ ID 3366, SEQ ID3369, SEQ ID 3370, SEQ ID 3390, SEQ ID 3392, SEQ ID 3393, SEQ ID 3394,SEQ ID 3395, SEQ ID 3396, SEQ ID 3397, SEQ ID 3398, SEQ ID 3399, SEQ ID3401, SEQ ID 3403, SEQ ID 3404, SEQ ID 3407, SEQ ID 3408, SEQ ID 3409,SEQ ID 3410, SEQ ID 3411, SEQ ID 3412, SEQ ID 3413, SEQ ID 3414, SEQ ID3415, SEQ ID 3417, SEQ ID 3419, SEQ ID 3420, SEQ ID 3422, SEQ ID 3423,SEQ ID 3424, SEQ ID 3428, SEQ ID 3429, SEQ ID 3430, SEQ ID 3432, SEQ ID3433, SEQ ID 3434, SEQ ID 3435, SEQ ID 3436, SEQ ID 3437, SEQ ID 3439,SEQ ID 3440, SEQ ID 3441, SEQ ID 3442, SEQ ID 3443, SEQ ID 3444, SEQ ID3445, SEQ ID 3446, SEQ ID 3447, SEQ ID 3448, SEQ ID 3449, SEQ ID 3450,SEQ ID 3451, SEQ ID 3452, SEQ ID 3460, SEQ ID 3461, SEQ ID 3466, SEQ ID3467, SEQ ID 3468, SEQ ID 3490, SEQ ID 3494, SEQ ID 3496, SEQ ID 3501,SEQ ID 3505, SEQ ID 3511, SEQ ID 3512, SEQ ID 3516, SEQ ID 3517, SEQ ID3521, SEQ ID 3522, SEQ ID 3556, SEQ ID 3557, SEQ ID 3561, SEQ ID 3566,SEQ ID 3567, SEQ ID 3568, SEQ ID 3569, SEQ ID 3571, SEQ ID 3572, SEQ ID3576, SEQ ID 3578, SEQ ID 3580, SEQ ID 3584, SEQ ID 3594, SEQ ID 3613,SEQ ID 3614, SEQ ID 3624, SEQ ID 3625, SEQ ID 3626, SEQ ID 3627, SEQ ID3628, SEQ ID 3633, SEQ ID 3641, SEQ ID 3643, SEQ ID 3648, SEQ ID 3651,SEQ ID 3654, SEQ ID 3656, SEQ ID 3659, SEQ ID 3660, SEQ ID 3661, SEQ ID3670, SEQ ID 3676, SEQ ID 3680, SEQ ID 3681, SEQ ID 3683, SEQ ID 3684,SEQ ID 3685, SEQ ID 3686, SEQ ID 3687, SEQ ID 3688, SEQ ID 3689, SEQ ID3691, SEQ ID 3693, SEQ ID 3694, SEQ ID 3695, SEQ ID 3696, SEQ ID 3698,SEQ ID 3700, SEQ ID 3701, SEQ ID 3703, SEQ ID 3704, SEQ ID 3707, SEQ ID3708, SEQ ID 3709, SEQ ID 3710, SEQ ID 3711, SEQ ID 3712, SEQ ID 3713,SEQ ID 3714, SEQ ID 3715, SEQ ID 3716, SEQ ID 3717, SEQ ID 3718, SEQ ID3719, SEQ ID 3720, SEQ ID 3721, SEQ ID 3722, SEQ ID 3723, SEQ ID 3725,SEQ ID 3744, SEQ ID 3747, SEQ ID 3748, SEQ ID 3749, SEQ ID 3750, SEQ ID3751, SEQ ID 3752, SEQ ID 3753, SEQ ID 3754, SEQ ID 3755, SEQ ID 3774,SEQ ID 3775, SEQ ID 3776, SEQ ID 3786, SEQ ID 3788, SEQ ID 3790, SEQ ID3791, SEQ ID 3793, SEQ ID 3794, SEQ ID 3795, SEQ ID 3796, SEQ ID 3797,SEQ ID 3798, SEQ ID 3799, SEQ ID 3800, SEQ ID 3801, SEQ ID 3802, SEQ ID3803, SEQ ID 3804, SEQ ID 3805, SEQ ID 3809, SEQ ID 3810, SEQ ID 3811,SEQ ID 3812, SEQ ID 3813, SEQ ID 3814, SEQ ID 3815, SEQ ID 3821, SEQ ID3822, SEQ ID 3823, SEQ ID 3824, SEQ ID 3825, SEQ ID 3826, SEQ ID 3827,SEQ ID 3828, SEQ ID 3830, SEQ ID 3831, SEQ ID 3832, SEQ ID 3834, SEQ ID3836, SEQ ID 3837, SEQ ID 3838, SEQ ID 3839, SEQ ID 3840, SEQ ID 3841,SEQ ID 3842, SEQ ID 3844, SEQ ID 3850, SEQ ID 3852, SEQ ID 3867, SEQ ID3868, SEQ ID 3870, SEQ ID 3871, SEQ ID 3872, SEQ ID 3873, SEQ ID 3874,SEQ ID 3875, SEQ ID 3876, SEQ ID 3879, SEQ ID 3880, SEQ ID 3881, SEQ ID3882, SEQ ID 3883, SEQ ID 3884, SEQ ID 3885, SEQ ID 3886, SEQ ID 3887,SEQ ID 3888, SEQ ID 3889, SEQ ID 3890, SEQ ID 3891, SEQ ID 3892, SEQ ID3893, SEQ ID 3894, SEQ ID 3895, SEQ ID 3896, SEQ ID 3897, SEQ ID 3908,SEQ ID 3909, SEQ ID 3910, SEQ ID 3911, SEQ ID 3912, SEQ ID 3913, SEQ ID3922, SEQ ID 3923, SEQ ID 3930, SEQ ID 3935, SEQ ID 3936, SEQ ID 3937,SEQ ID 3938, SEQ ID 3939, SEQ ID 3940, SEQ ID 3944, SEQ ID 3945, SEQ ID3946, SEQ ID 3947, and SEQ ID 3948.

In some embodiments the oligonucleotide comprises the contiguousnucleotide sequence, and may optionally comprise further nucleotide(s),for example a nucleotide linker region which may be used to attach afunctional group (e.g. a conjugate group) to the contiguous nucleotidesequence. The nucleotide linker region may or may not be complementaryto the target nucleic acid. It is understood that the contiguousnucleotide sequence of the oligonucleotide cannot be longer than theoligonucleotide as such and that the oligonucleotide cannot be shorterthan the contiguous nucleotide sequence.

Nucleotides and Nucleosides

Nucleotides and nucleosides are the building blocks of oligonucleotidesand polynucleotides, and for the purposes of the present inventioninclude both naturally occurring and non-naturally occurring nucleotidesand nucleosides. In nature, nucleotides, such as DNA and RNA nucleotidescomprise a ribose sugar moiety, a nucleobase moiety and one or morephosphate groups (which is absent in nucleosides). Nucleosides andnucleotides may also interchangeably be referred to as “units” or“monomers”.

Modified Nucleoside

Advantageously, the antisense oligonucleotide progranulin agonist of theinvention may comprise one or more modified nucleoside.

The term “modified nucleoside” or “nucleoside modification” as usedherein refers to nucleosides modified as compared to the equivalent DNAor RNA nucleoside by the introduction of one or more modifications ofthe sugar moiety or the (nucleo)base moiety. Advantageously, one or moreof the modified nucleosides of the antisense oligonucleotides of theinvention may comprise a modified sugar moiety. The term modifiednucleoside may also be used herein interchangeably with the term“nucleoside analogue” or modified “units” or modified “monomers”.Nucleosides with an unmodified DNA or RNA sugar moiety are termed DNA orRNA nucleosides herein. Nucleosides with modifications in the baseregion of the DNA or RNA nucleoside are still generally termed DNA orRNA if they allow Watson Crick base pairing. Exemplary modifiednucleosides which may be used in the antisense oligonucleotideprogranulin agonists of the invention include LNA, 2′-O-MOE, 2′oMe andmorpholino nucleoside analogues.

Modified Internucleoside Linkage

Advantageously, the antisense oligonucleotide progranulin agonist of theinvention comprises one or more modified internucleoside linkage.

The term “modified internucleoside linkage” is defined as generallyunderstood by the skilled person as linkages other than phosphodiester(PO) linkages, that covalently couple two nucleosides together. Theantisense oligonucleotide progranulin agonists of the invention maytherefore comprise one or more modified internucleoside linkages such asone or more phosphorothioate internucleoside linkage.

In some embodiments at least 50% of the internucleoside linkages in theantisense oligonucleotide progranulin agonist, or contiguous nucleotidesequence thereof, are phosphorothioate, such as at least 60%, such as atleast 70%, such as at least 75%, such as at least 80%, such as at least90% or more of the internucleoside linkages in the antisenseoligonucleotide progranulin agonist, or contiguous nucleotide sequencethereof, are phosphorothioate. In some embodiments all of theinternucleoside linkages of the antisense oligonucleotide progranulinagonist, or contiguous nucleotide sequence thereof, arephosphorothioate.

Advantageously, all the internucleoside linkages of the contiguousnucleotide sequence of the antisense oligonucleotide progranulin agonistmay be phosphorothioate, or all the internucleoside linkages of theantisense oligonucleotide progranulin agonist may be phosphorothioatelinkages.

Nucleobase

The term nucleobase includes the purine (e.g. adenine and guanine) andpyrimidine (e.g. uracil, thymine and cytosine) moiety present innucleosides and nucleotides which form hydrogen bonds in nucleic acidhybridization. In the context of the present invention the termnucleobase also encompasses modified nucleobases which may differ fromnaturally occurring nucleobases, but which are functional during nucleicacid hybridization. In this context “nucleobase” refers to bothnaturally occurring nucleobases such as adenine, guanine, cytosine,thymidine, uracil, xanthine and hypoxanthine, as well as non-naturallyoccurring variants. Such variants are for example described in Hirao etal (2012) Accounts of Chemical Research vol 45 page 2055 and Bergstrom(2009) Current Protocols in Nucleic Acid Chemistry Suppl. 37 1.4.1.

In some embodiments the nucleobase moiety is modified by changing thepurine or pyrimidine into a modified purine or pyrimidine, such assubstituted purine or substituted pyrimidine, such as a nucleobaseselected from isocytosine, pseudoisocytosine, 5-methyl cytosine,5-thiozolo-cytosine, 5-propynyl-cytosine, 5-propynyl-uracil,5-bromouracil 5-thiazolo-uracil, 2-thio-uracil, 2′thio-thymine, inosine,diaminopurine, 6-aminopurine, 2-aminopurine, 2,6-diaminopurine and2-chloro-6-aminopurine.

The nucleobase moieties may be indicated by the letter code for eachcorresponding nucleobase, e.g. A, T, G, C or U, wherein each letter mayoptionally include modified nucleobases of equivalent function. Forexample, in the exemplified oligonucleotides, the nucleobase moietiesare selected from A, T, G, C, and 5-methyl cytosine. Optionally, for LNAgapmers, 5-methyl cytosine LNA nucleosides may be used.

Modified Oligonucleotide

The antisense oligonucleotide progranulin agonist of the invention maybe a modified oligonucleotide.

The term modified oligonucleotide describes an oligonucleotidecomprising one or more sugar-modified nucleosides and/or modifiedinternucleoside linkages. The term “chimeric oligonucleotide” is a termthat has been used in the literature to describe oligonucleotidescomprising sugar modified nucleosides and DNA nucleosides. In someembodiments, it may be advantageous for the antisense oligonucleotideprogranulin agonist of the invention to be a chimeric oligonucleotide.

Complementarity

The term “complementarity” describes the capacity for Watson-Crickbase-pairing of nucleosides/nucleotides. Watson-Crick base pairs areguanine (G)-cytosine (C) and adenine (A)-thymine (T)/uracil (U).

It will be understood that oligonucleotides may comprise nucleosideswith modified nucleobases, for example 5-methyl cytosine is often usedin place of cytosine, and as such the term complementarity encompassesWatson Crick base-paring between non-modified and modified nucleobases(see for example Hirao et al (2012) Accounts of Chemical Research vol 45page 2055 and Bergstrom (2009) Current Protocols in Nucleic AcidChemistry Suppl. 37 1.4.1).

The term “% complementary” as used herein, refers to the proportion ofnucleotides (in percent) of a contiguous nucleotide sequence in anucleic acid molecule (e.g. oligonucleotide) which across the contiguousnucleotide sequence, are complementary to a reference sequence (e.g. atarget sequence or sequence motif). The percentage of complementarity isthus calculated by counting the number of aligned nucleobases that arecomplementary (from Watson Crick base pairs) between the two sequences(when aligned with the target sequence 5′-3′ and the oligonucleotidesequence from 3′-5′), dividing that number by the total number ofnucleotides in the oligonucleotide and multiplying by 100. In such acomparison a nucleobase/nucleotide which does not align (form a basepair) is termed a mismatch. Insertions and deletions are not allowed inthe calculation of complementarity of a contiguous nucleotide sequence.It will be understood that in determining complementarity, chemicalmodifications of the nucleobases are disregarded as long as thefunctional capacity of the nucleobase to form Watson Crick base pairingis retained (e.g. 5′-methyl cytosine is considered identical to acytosine for the purpose of calculating % identity).

Within the present invention the term “complementary” requires theantisense oligonucleotide progranulin agonist to be at least about 80%complementary, or at least about 90% complementary, to a humanprogranulin precursor-mRNA (pre-mRNA) or mature mRNA transcript. In someembodiments the antisense oligonucleotide progranulin agonist may be atleast about 80%, at least about 81%, at least about 82%, at least about83%, at least about 84%, at least about 85%, at least about 86%, atleast about 87%, at least about 88%, at least about 89%, at least about90%, at least about 91%, at least about 92%, at least about 93%, atleast about 94%, at least about 95%, at least about 96%, at least about97%, at least about 98% or at least about 99% complementary to a humanprogranulin precursor-mRNA (pre-mRNA) or mature mRNA transcript. Putanother way, for some embodiments, an antisense oligonucleotideprogranulin agonist of the invention may include one, two, three or moremis-matches, wherein a mis-match is a nucleotide within the antisenseoligonucleotide progranulin agonist of the invention which does not basepair with its target.

The term “fully complementary”, refers to 100% complementarity.

The antisense oligonucleotide progranulin agonists of the invention areadvantageously complementary to the human progranulin precursor mRNA(pre-mRNA) or the human prograulin mature mRNA sequence. The humanprogranulin mature mRNA sequence is exemplified herein as SEQ ID NO 1.The human progranulin precursor-mRNA (pre-mRNA) sequence is exemplifiedherein as SEQ ID NO 3949. SEQ ID NO 1 and SEQ ID NO 3949 are providedherein as reference sequences and it will be understood that the targetprogranulin nucleic acid may be an allelic variant of SEQ ID NO 1 or SEQID NO 3949, such as an allelic variant which comprises one or morepolymorphism in the human progranulin nucleic acid sequence.

Identity

The term “identity” as used herein, refers to the proportion ofnucleotides (expressed in percent) of a contiguous nucleotide sequencein a nucleic acid molecule (e.g. oligonucleotide) which across thecontiguous nucleotide sequence, are identical to a reference sequence(e.g. a sequence motif).

The percentage of identity is thus calculated by counting the number ofaligned nucleobases that are identical (a Match) between two sequences(in the contiguous nucleotide sequence of the compound of the inventionand in the reference sequence), dividing that number by the total numberof nucleotides in the oligonucleotide and multiplying by 100. Therefore,Percentage of Identity=(Matches×100)/Length of aligned region (e.g. thecontiguous nucleotide sequence). Insertions and deletions are notallowed in the calculation the percentage of identity of a contiguousnucleotide sequence. It will be understood that in determining identity,chemical modifications of the nucleobases are disregarded as long as thefunctional capacity of the nucleobase to form Watson Crick base pairingis retained (e.g. 5-methyl cytosine is considered identical to acytosine for the purpose of calculating % identity).

Hybridization

The terms “hybridizing” or “hybridizes” as used herein are to beunderstood as two nucleic acid strands (e.g. an oligonucleotide and atarget nucleic acid) forming hydrogen bonds between base pairs onopposite strands thereby forming a duplex. The affinity of the bindingbetween two nucleic acid strands is the strength of the hybridization.It is often described in terms of the melting temperature (T_(m))defined as the temperature at which half of the oligonucleotides areduplexed with the target nucleic acid. At physiological conditions T_(m)is not strictly proportional to the affinity (Mergny and Lacroix, 2003,Oligonucleotides 13:515-537). The standard state Gibbs free energy ΔG°is a more accurate representation of binding affinity and is related tothe dissociation constant (K_(d)) of the reaction by ΔG°=−RTln(K_(d)),where R is the gas constant and T is the absolute temperature.Therefore, a very low ΔG° of the reaction between an oligonucleotide andthe target nucleic acid reflects a strong hybridization between theoligonucleotide and target nucleic acid. ΔG° is the energy associatedwith a reaction where aqueous concentrations are 1M, the pH is 7, andthe temperature is 37° C. The hybridization of oligonucleotides to atarget nucleic acid is a spontaneous reaction and for spontaneousreactions ΔG° is less than zero. ΔG° can be measured experimentally, forexample, by use of the isothermal titration calorimetry (ITC) method asdescribed in Hansen et al., 1965, Chem. Comm. 36-38 and Holdgate et al.,2005, Drug Discov Today. The skilled person will know that commercialequipment is available for ΔG° measurements. ΔG° can also be estimatednumerically by using the nearest neighbor model as described bySantaLucia, 1998, Proc Natl Acad Sci USA. 95: 1460-1465 usingappropriately derived thermodynamic parameters described by Sugimoto etal., 1995, Biochemistry 34:11211-11216 and McTigue et al., 2004,Biochemistry 43:5388-5405.

In some embodiments, antisense oligonucleotide progranulin agonists ofthe present invention hybridize to a target nucleic acid with estimatedΔG° values below −10 kcal for oligonucleotides that are 10-30nucleotides in length.

In some embodiments the degree or strength of hybridization is measuredby the standard state Gibbs free energy ΔG°. The oligonucleotides mayhybridize to a target nucleic acid with estimated ΔG° values below therange of −10 kcal, such as below −15 kcal, such as below −20 kcal andsuch as below −25 kcal for oligonucleotides that are 8-30 nucleotides inlength. In some embodiments the oligonucleotides hybridize to a targetnucleic acid with an estimated ΔG° value of −10 to −60 kcal, such as −12to −40, such as from −15 to −30 kcal, or −16 to −27 kcal such as −18 to−25 kcal.

High Affinity Modified Nucleosides

A high affinity modified nucleoside is a modified nucleotide which, whenincorporated into the oligonucleotide enhances the affinity of theoligonucleotide for its complementary target, for example as measured bythe melting temperature (T^(m)). A high affinity modified nucleoside ofthe present invention preferably results in an increase in meltingtemperature between +0.5 to +12° C., more preferably between +1.5 to+10° C. and most preferably between +3 to +8° C. per modifiednucleoside. Numerous high affinity modified nucleosides are known in theart and include for example, many 2′ substituted nucleosides as well aslocked nucleic acids (LNA) (see e.g. Freier & Altmann; Nucl. Acid Res.,1997, 25, 4429-4443 and Uhlmann; Curr. Opinion in Drug Development,2000, 3(2), 293-213).

Sugar Modifications

The antisense oligonucleotide progranulin agonist of the invention maycomprise one or more nucleosides which have a modified sugar moiety,i.e. a modification of the sugar moiety when compared to the ribosesugar moiety found in DNA and RNA.

Numerous nucleosides with modification of the ribose sugar moiety havebeen made, primarily with the aim of improving certain properties ofoligonucleotides, such as affinity and/or nuclease resistance.

Such modifications include those where the ribose ring structure ismodified, e.g. by replacement with a hexose ring (HNA), or a bicyclicring, which typically have a biradicle bridge between the C2 and C4carbons on the ribose ring (LNA), or an unlinked ribose ring whichtypically lacks a bond between the C2 and C3 carbons (e.g. UNA). Othersugar modified nucleosides include, for example, bicyclohexose nucleicacids (WO2011/017521) or tricyclic nucleic acids (WO2013/154798).Modified nucleosides also include nucleosides where the sugar moiety isreplaced with a non-sugar moiety, for example in the case of peptidenucleic acids (PNA), or morpholino nucleic acids.

Sugar modifications also include modifications made via altering thesubstituent groups on the ribose ring to groups other than hydrogen, orthe 2′-OH group naturally found in DNA and RNA nucleosides. Substituentsmay, for example be introduced at the 2′, 3′, 4′ or 5′ positions.

2′ Sugar Modified Nucleosides

A 2′ sugar modified nucleoside is a nucleoside which has a substituentother than H or —OH at the 2′ position (2′ substituted nucleoside) orcomprises a 2′ linked biradicle capable of forming a bridge between the2′ carbon and a second carbon in the ribose ring, such as LNA (2′-4′biradicle bridged) nucleosides.

Indeed, much focus has been spent on developing 2′ sugar substitutednucleosides, and numerous 2′ substituted nucleosides have been found tohave beneficial properties when incorporated into oligonucleotides. Forexample, the 2′ modified sugar may provide enhanced binding affinityand/or increased nuclease resistance to the oligonucleotide. Examples of2′ substituted modified nucleosides are 2′-O-alkyl-RNA, 2′-O-methyl-RNA(2′oMe), 2′-alkoxy-RNA, 2′-O-methoxyethyl-RNA (MOE), 2′-amino-DNA,2′-Fluoro-RNA, and 2′-F-ANA nucleoside. For further examples, please seee.g. Freier & Altmann; Nucl. Acid Res., 1997, 25, 4429-4443 and Uhlmann;Curr. Opinion in Drug Development, 2000, 3(2), 293-213, and Deleavey andDamha, Chemistry and Biology 2012, 19, 937. Below are illustrations ofsome 2′ substituted modified nucleosides.

In relation to the present invention 2′ substituted sugar modifiednucleosides does not include 2′ bridged nucleosides like LNA.

Locked Nucleic Acid Nucleosides (LNA Nucleoside)

A “LNA nucleoside” is a 2′-modified nucleoside which comprises abiradical linking the C2′ and C4′ of the ribose sugar ring of saidnucleoside (also referred to as a “2′-4′ bridge”), which restricts orlocks the conformation of the ribose ring. These nucleosides are alsotermed bridged nucleic acid or bicyclic nucleic acid (BNA) in theliterature. The locking of the conformation of the ribose is associatedwith an enhanced affinity of hybridization (duplex stabilization) whenthe LNA is incorporated into an oligonucleotide for a complementary RNAor DNA molecule. This can be routinely determined by measuring themelting temperature of the oligonucleotide/complement duplex.

Non limiting, exemplary LNA nucleosides are disclosed in WO 99/014226,WO 00/66604, WO 98/039352, WO 2004/046160, WO 00/047599, WO 2007/134181,WO 2010/077578, WO 2010/036698, WO 2007/090071, WO 2009/006478, WO2011/156202, WO 2008/154401, WO 2009/067647, WO 2008/150729, Morita etal., Bioorganic & Med. Chem. Lett. 12, 73-76, Seth et al. J. Org. Chem.2010, Vol 75(5) pp. 1569-81, and Mitsuoka et al., Nucleic Acids Research2009, 37(4), 1225-1238, and Wan and Seth, J. Medical Chemistry 2016, 59,9645-9667.

Further non limiting, exemplary LNA nucleosides are disclosed in Scheme1.

Particular LNA nucleosides are beta-D-oxy-LNA, 6′-methyl-beta-D-oxy LNAsuch as (S)-6′-methyl-beta-D-oxy-LNA (ScET) and ENA.

A particularly advantageous LNA is beta-D-oxy-LNA.

Morpholino Oligonucleotides

In some embodiments, the antisense oligonucleotide progranulin agonistof the invention comprises or consists of morpholino nucleosides (i.e.is a Morpholino oligomer and as a phosphorodiamidate Morpholino oligomer(PMO)). Splice modulating morpholino oligonucleotides have been approvedfor clinical use—see for example eteplirsen, a 30nt morpholinooligonucleotide targeting a frame shift mutation in DMD, used to treatDuchenne muscular dystrophy. Morpholino oligonucleotides havenucleobases attached to six membered morpholine rings rather ribose,such as methylenemorpholine rings linked through phosphorodiamidategroups, for example as illustrated by the following illustration of 4consecutive morpholino nucleotides:

In some embodiments, morpholino oligonucleotides of the invention maybe, for example 20-40 morpholino nucleotides in length, such asmorpholino 25-35 nucleotides in length.

RNase H Activity and Recruitment

The RNase H activity of an antisense oligonucleotide refers to itsability to recruit RNase H when in a duplex with a complementary RNAmolecule. WO01/23613 provides in vitro methods for determining RNaseHactivity, which may be used to determine the ability to recruit RNaseH.Typically an oligonucleotide is deemed capable of recruiting RNase H ifit, when provided with a complementary target nucleic acid sequence, hasan initial rate, as measured in pmol/l/min, of at least 5%, such as atleast 10%, at least 20% or more than 20%, of the initial rate determinedwhen using an oligonucleotide having the same base sequence as themodified oligonucleotide being tested, but containing only DNA monomerswith phosphorothioate linkages between all monomers in theoligonucleotide, and using the methodology provided by Examples 91-95 ofWO01/23613 (hereby incorporated by reference). For use in determiningRHase H activity, recombinant RNase H1 is available from Lubio ScienceGmbH, Lucerne, Switzerland.

DNA oligonucleotides are known to effectively recruit RNaseH, as aregapmer oligonucleotides which comprise a region of DNA nucleosides(typically at least 5 or 6 contiguous DNA nucleosides), flanked 5′ and3′ by regions comprising 2′ sugar modified nucleosides, typically highaffinity 2′ sugar modified nucleosides, such as 2-O-MOE and/or LNA. Foreffective modulation of splicing, degradation of the pre-mRNA is notdesirable, and as such it is preferable to avoid the RNaseH degradationof the target. Therefore, the antisense oligonucleotide progranulinagonists of the invention are not RNaseH recruiting gapmeroligonucleotide.

RNaseH recruitment may be avoided by limiting the number of contiguousDNA nucleotides in the oligonucleotide—therefore mimxes and totalmerdesigns may be used. Advanateously the antisense oligonucleotideprogranulin agonistd of the invention, or the contiguous nucleotidesequence thereof, do not comprise more than 3 contiguous DNAnucleosides. Further, advanateously the antisense oligonucleotideprogranulin agonists of the invention, or the contiguous nucleotidesequence thereof, do not comprise more than 4 contiguous DNAnucleosides. Further advantageously, the progranulin agonist antisenseoligonucleotide agonists of the invention, or contiguous nucleotidesequence thereof, do not comprise more than 2 contiguous DNAnucleosides.

Mixmers and Totalmers

For splice modulation it is often advantageous to use antisenseoligonucleotides which do not recruit RNAaseH. As RNaseH activityrequires a contiguous sequence of DNA nucleotides, RNaseH activity ofantisense oligonucleotide may be achieved by designing antisenseoligonucleotides which do not comprise a region of more than 3 or morethan 4 contiguous DNA nucleosides. This may be achieved by usingantisense oligonucleotides or contiguous nucleoside regions thereof witha mixmer design, which comprise sugar modified nucleosides, such as 2′sugar modified nucleosides, and short regions of DNA nucleosides, suchas 1, 2 or 3 DNA nucleosides. Mixmers are exemplified herein by everysecond design, wherein the nucleosides alternate between 1 LNA and 1 DNAnucleoside, e.g. LDLDLDLDLDLDLDLL, with 5′ and 3′ terminal LNAnucleosides, and every third design, such as LDDLDDLDDLDDLDDL, whereevery third nucleoside is a LNA nucleoside.

A totalmer is an antisense oligonucleotide or a contiguous nucleotidesequence thereof which does not comprise DNA or RNA nucleosides, and mayfor example comprise only 2′-O-MOE nucleosides, such as a fully MOEphosphorothioate, e.g. MMMMMMMMMMMMMMMMMMMM, where M=2′-O-MOE, or mayfor example comprise only 2′oMe nucleosides, which are reported to beeffective splice modulators for therapeutic use.

Alternatively, a mixmer may comprise a mixture of modified nucleosides,such as MLMLMLMLMLMLMLMLMLML, wherein L=LNA and M=2′-O-MOE nucleosides.Advantageously, the internucleoside nucleosides in mixmers and totalmersmay be phosphorothioate, or a majority of nucleoside linkages in mixmersmay be phosphorothioate. Mixmers and totalmers may comprise otherinternucleoside linkages, such as phosphodiester or phosphorodithioate,by way of example.

Region D′ or D″ in an Oligonucleotide

The antisense oligonucleotide progranulin agonist of the invention mayin some embodiments comprise or consist of the contiguous nucleotidesequence of the oligonucleotide which is complementary to the targetnucleic acid, such as a mixmer or toalmer region, and further 5′ and/or3′ nucleosides. The further 5′ and/or 3′ nucleosides may or may not becomplementary, such as fully complementary, to the target nucleic acid.Such further 5′ and/or 3′ nucleosides may be referred to as region D′and D″ herein.

The addition of region D′ or D″ may be used for the purpose of joiningthe contiguous nucleotide sequence, such as the mixmer or totoalmer, toa conjugate moiety or another functional group. When used for joiningthe contiguous nucleotide sequence with a conjugate moiety is can serveas a biocleavable linker. Alternatively, it may be used to provideexonucleoase protection or for ease of synthesis or manufacture.

Region D′ or D″ may independently comprise or consist of 1, 2, 3, 4 or 5additional nucleotides, which may be complementary or non-complementaryto the target nucleic acid. The nucleotide adjacent to the F or F′region is not a sugar-modified nucleotide, such as a DNA or RNA or basemodified versions of these. The D′ or D′ region may serve as a nucleasesusceptible biocleavable linker (see definition of linkers). In someembodiments the additional 5′ and/or 3′ end nucleotides are linked withphosphodiester linkages, and are DNA or RNA. Nucleotide basedbiocleavable linkers suitable for use as region D′ or D″ are disclosedin WO2014/076195, which include by way of example a phosphodiesterlinked DNA dinucleotide. The use of biocleavable linkers inpoly-oligonucleotide constructs is disclosed in WO2015/113922, wherethey are used to link multiple antisense constructs within a singleoligonucleotide.

In one embodiment the antisense oligonucleotide progranulin agonist ofthe invention comprises a region D′ and/or D″ in addition to thecontiguous nucleotide sequence which constitutes a mixmer or a totalmer.

In some embodiments the internucleoside linkage positioned betweenregion D′ or D″ and the mixmer or totalmer region is a phosphodiesterlinkage.

Conjugate

The invention encompasses an antisense oligonucleotide progranulinagonist covalently attached to at least one conjugate moiety. In someembodiments this may be referred to as a conjugate of the invention.

The term “conjugate” as used herein refers to an antisenseoligonucleotide progranulin agonist which is covalently linked to anon-nucleotide moiety (conjugate moiety or region C or third region).The conjugate moiety may be covalentaly linked to the antisenseoligonucleotide, optionally via a linker group, such as region D′ or D″.

Oligonucleotide conjugates and their synthesis has also been reported incomprehensive reviews by Manoharan in Antisense Drug Technology,Principles, Strategies, and Applications, S. T. Crooke, ed., Ch. 16,Marcel Dekker, Inc., 2001 and Manoharan, Antisense and Nucleic Acid DrugDevelopment, 2002, 12, 103.

In some embodiments, the non-nucleotide moiety (conjugate moiety) isselected from the group consisting of carbohydrates (e.g. GalNAc), cellsurface receptor ligands, drug substances, hormones, lipophilicsubstances, polymers, proteins, peptides, toxins (e.g. bacterialtoxins), vitamins, viral proteins (e.g. capsids) or combinationsthereof.

Linkers

A linkage or linker is a connection between two atoms that links onechemical group or segment of interest to another chemical group orsegment of interest via one or more covalent bonds. Conjugate moietiescan be attached to the antisense oligonucleotide progranulin agonistdirectly or through a linking moiety (e.g. linker or tether). Linkersserve to covalently connect a third region, e.g. a conjugate moiety(Region C), to a first region, e.g. an oligonucleotide or contiguousnucleotide sequence complementary to the target nucleic acid (region A).

In some embodiments of the invention the conjugate or antisenseoligonucleotide progranulin agonist conjugate of the invention mayoptionally comprise a linker region (second region or region B and/orregion Y) which is positioned between the oligonucleotide or contiguousnucleotide sequence complementary to the target nucleic acid (region Aor first region) and the conjugate moiety (region C or third region).

Region B refers to biocleavable linkers comprising or consisting of aphysiologically labile bond that is cleavable under conditions normallyencountered or analogous to those encountered within a mammalian body.Conditions under which physiologically labile linkers undergo chemicaltransformation (e.g., cleavage) include chemical conditions such as pH,temperature, oxidative or reductive conditions or agents, and saltconcentration found in or analogous to those encountered in mammaliancells. Mammalian intracellular conditions also include the presence ofenzymatic activity normally present in a mammalian cell such as fromproteolytic enzymes or hydrolytic enzymes or nucleases. In oneembodiment the biocleavable linker is susceptible to S1 nucleasecleavage. In some embodiments the nuclease susceptible linker comprisesbetween 1 and 5 nucleosides, such as DNA nucleoside(s) comprising atleast two consecutive phosphodiester linkages. Phosphodiester containingbiocleavable linkers are described in more detail in WO 2014/076195.

Region Y refers to linkers that are not necessarily biocleavable butprimarily serve to covalently connect a conjugate moiety (region C orthird region), to an oligonucleotide (region A or first region). Theregion Y linkers may comprise a chain structure or an oligomer ofrepeating units such as ethylene glycol, amino acid units or amino alkylgroups The antisense oligonucleotide progranulin agonist conjugates ofthe present invention can be constructed of the following regionalelements A-C, A-B-C, A-B-Y-C, A-Y-B-C or A-Y-C. In some embodiments thelinker (region Y) is an amino alkyl, such as a C2-C36 amino alkyl group,including, for example C6 to C12 amino alkyl groups. In some embodimentsthe linker (region Y) is a C6 amino alkyl group.

Treatment

The term ‘treatment’ as used herein refers to both treatment of anexisting disease (e.g. a disease or disorder as herein referred to), orprevention of a disease, i.e. prophylaxis. It will therefore berecognized that treatment as referred to herein may, in someembodiments, be prophylactic.

DETAILED DESCRIPTION OF THE INVENTION

The inventors have identified that the expression level of theprogranulin transcript can be effectively enhanced by targeting theprogranulin precursor-mRNA (pre-mRNA) transcript or the progranulinmature mRNA sequence with antisense oligonucleotides, particularlyantisense oligonucleotides which comprise high affinity sugar modifiednucleosides, such as high affinity 2′ sugar modified nucleosides, suchas LNA nucleosides or 2′-O-methoxyethyl (MOE) nucleosides.

Described herein are target sites present on the human progranulinnucleic acid target, such as a progranulin precursor-mRNA (pre-mRNA) ormature mRNA sequence, which can be targeted by antisense oligonucleotideagonists of progranulin.

The inventors have surprisingly determined that targeting the 5′ UTR and3′ UTR of the progranulin mature mRNA can be particularly effective.

The 5′ UTR contains upstream start sites (AUG sites), also known asupstream open reading frames (uORFs). Without wishing to be bound bytheory, it is considered that the antisense oligonucleotide progranulinagonists of the invention can increase progranulin production by bindingto these regions and affecting, such as reducing, protein translationfrom these upstream AUG sites. This ensures that protein translation isinitiated from the downstream canonical start site (ORF), increasingprogranulin production.

The 3′ UTR contains binding sites for microRNAs. Without wishing to bebound by theory, it is considered that the antisense oligonucleotideprogranulin agonists of the invention may regulate gene expression bybinding to these sites in the 3′UTR and preventing microRNA-inducedrepression of gene expression, leading to increased progranulinproduction.

Oligonucleotides, such as RNaseH recruiting single stranded antisenseoligonucleotides or siRNAs are used extensively in the art to inhibittarget RNAs—i.e. are used as antagonists of their complementary nucleicacid target.

The antisense oligonucleotide of the present invention are agonists,i.e. enhance the expression of their complementary target, progranulinnucleic acids, and thereby enhance the expression of progranulinprotein. Enhanced progranulin expression is desirable to treat a rangeof neurological disorders, such as TDP-43 pathologies, or disorderswhich are characterized by, or caused by progranulin haploinsufficiency.

In certain embodiments the antisense oligonucleotide progranulinagonists of the present invention may enhance the production of theircomplementary target, progranulin nucleic acids, by at least about 10%.In other embodiments the antisense oligonucleotide progranulin agonistsof the present invention may enhance the production of theircomplementary target, progranulin nucleic acids, by at least about 15%,at least about 20%, at least about 25%, at least about 30%, at leastabout 35%, at least about 40%, at least about 45%, at least about 50% ormore, at least about 60% or more, at least about 70% or more, at leastabout 80% or more, at least about 90% or more, at least about 100% ormore, at least about 200% or more, at least about 300% or more, at leastabout 400% or more, or at least about 500% or more.

In some embodiments, the antisense oligonucleotide progranulin agonistof the invention or the contiguous nucleotide sequence thereof comprisesor consists of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40contiguous nucleotides in length.

In some embodiments, the entire nucleotide sequence of the antisenseoligonucleotide is the contiguous nucleotide sequence.

In some embodiments the contiguous nucleotide sequence is complementaryto a 5′UTR region of a human progranulin mature mRNA transcript. Thecontiguous nucleotide sequence may be fully complementary to a 5′UTRregion of a human progranulin mature mRNA transcript. As indicatedabove, and without wishing to be bound by theory, targeting the 5′UTRmay increase progranulin expression by binding to upstream start sites(AUG sites) and affecting, such as reducing, protein translation fromthese upstream AUG sites. This ensures that protein translation isinitiated from the downstream canonical start site (ORF), increasingprogranulin production.

In some embodiments the contiguous nucleotide sequence may becomplementary to SEQ ID NO 2, SEQ ID NO 689, SEQ ID NO 683, SEQ ID NO684, SEQ ID NO 685, SEQ ID NO 686, SEQ ID NO 687, SEQ ID NO 688, or asequence selected from the group consisting of SEQ ID NO 343-586.

In another embodiment the contiguous nucleotide sequence may becomplementary to nucleotides 38-246 of SEQ ID NO 1.

In another embodiment the contiguous nucleotide sequence may be fullycomplementary to SEQ ID NO 2, or SEQ ID NO 689.

In another embodiment the contiguous nucleotide sequence may be fullycomplementary to a sequence selected from the group consisting of SEQ IDNO 568, SEQ ID NO 571, SEQ ID NO 575, SEQ ID NO 576, SEQ ID NO 577, SEQID NO 578, SEQ ID NO 584 & SEQ ID NO 586.

In one embodiment the contiguous nucleotide sequence may a sequenceselected from the group consisting of SEQ ID NO 3-342. The inventionalso contemplates fragements of these contiguous nucleotide sequences,including fragments of at least 8, at least 9, at least 10, at least 11,at least 12, at least 13, at least 14, at least 15, at least 16 or atleast 17 contiguous nucleotides thereof.

In certain embodiments the contiguous nucleotide sequence may beselected from the group consisting of SEQ ID NO 105, SEQ ID NO 106, SEQID NO 110, SEQ ID NO 113, SEQ ID NO 114, SEQ ID NO 231 and SEQ ID NO241. The invention also contemplates fragements of these contiguousnucleotide sequences, including fragments of at least 8, at least 9, atleast 10, at least 11, at least 12, at least 13, at least 14, at least15, at least 16 or at least 17 contiguous nucleotides thereof.

In some embodiments the contiguous nucleotide sequence is complementaryto a 3′UTR region of a human progranulin mature mRNA transcript. Thecontiguous nucleotide sequence may be fully complementary to a 3′UTRregion of a human progranulin mature mRNA transcript. As indicatedabove, and without wishing to be bound by theory, the antisenseoligonucleotide progranulin agonists of the invention may regulate geneexpression by binding to microRNA sites in the 3′UTR and preventingmicroRNA-induced repression of gene expression, leading to increasedprogranulin production.

In some embodiments the contiguous nucleotide sequence may becomplementary to SEQ ID NO 684, SEQ ID NO 685, SEQ ID NO 686, SEQ ID NO687, SEQ ID NO 688, or a sequence selected from the group consisting ofSEQ ID NO 587-682.

In another embodiment the contiguous nucleotide sequence may becomplementary to nucleotides 2039-2346 of SEQ ID NO 1.

In another embodiment the contiguous nucleotide sequence may be fullycomplementary to SEQ ID NO 684, SEQ ID NO 685, SEQ ID NO 686, SEQ ID NO687, and SEQ ID NO 688.

In another embodiment the contiguous nucleotide sequence may be fullycomplementary to a sequence selected from the group consisting of SEQ IDNOs 607, SEQ ID NO 608, SEQ ID NO 609, SEQ ID NO 610, SEQ ID NO 611, SEQID NO 612, SEQ ID NO 619, SEQ ID NO 620, SEQ ID NO 633, SEQ ID NO 640,SEQ ID NO 641, SEQ ID NO 645, SEQ ID NO 651, and SEQ ID NO 652.

In some embodiments, the antisense oligonucleotide progranulin agonistor contiguous nucleotide sequence comprises or consists of a sequenceselected from the group consisting of sequences SEQ ID NO 3-342. It willbe understood that the sequences shown in SEQ ID NO 3-342 may includemodified nucleobases which function as the shown nucleobase in basepairing, for example 5-methyl cytosine may be used in place of methylcytosine. Inosine may be used as a universal base.

In some embodiments, the antisense oligonucleotide progranulin agonistor contiguous nucleotide sequence comprises or consists of 8 to 30 or 8to 40 nucleotides in length with at least 90% identity, preferably 100%identity, to a sequence selected from the group consisting of SEQ ID NO:3 to 342. In some embodiments the antisense oligonucleotide progranulinagonist may be 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40nucleotides in length.

Without wishing to be bound by theory, it is considered that theantisense oligonucleotide progranulin agonists of the invention whichbind to target sites outside the 5′ UTR and 3′ UTR regions of theprogranulin mature mRNA may increase progranulin protein expression.This increased progranulin protein expression may occur as a result ofeffects of the antisense oligonucleotide progranulin agonists onsecondary regulatory mRNA structures and/or on binding of RNA bindingproteins that would otherwise negatively affect protein translation orprogranulin mRNA stability.

It is understood that the contiguous nucleobase sequences (motifsequence) can be modified to for example increase nuclease resistanceand/or binding affinity to the target nucleic acid.

The pattern in which the modified nucleosides (such as high affinitymodified nucleosides) are incorporated into the oligonucleotide sequenceis generally termed oligonucleotide design.

The antisense oligonucleotide progranulin agonists of the invention aredesigned with modified nucleosides and DNA nucleosides. Advantageously,high affinity modified nucleosides are used.

In an embodiment, the oligonucleotide comprises at least 1 modifiednucleoside, such as at least 2, at least 3, at least 4, at least 5, atleast 6, at least 7, at least 8, at least 9, at least 10, at least 11,at least 12, at least 13, at least 14, at least 15 or at least 16modified nucleosides.

In an embodiment the oligonucleotide comprises from 1 to 10 modifiednucleosides, such as from 2 to 9 modified nucleosides, such as from 3 to8 modified nucleosides, such as from 4 to 7 modified nucleosides, suchas 6 or 7 modified nucleosides. Suitable modifications are described inthe “Definitions” section under “modified nucleoside”, “high affinitymodified nucleosides”, “sugar modifications”, “2′ sugar modifications”and Locked nucleic acids (LNA)”.

In an embodiment, the antisense oligonucleotide progranulin agonistcomprises one or more sugar modified nucleosides, such as 2′ sugarmodified nucleosides. Preferably the antisense oligonucleotideprogranulin agonist of the invention comprises one or more 2′ sugarmodified nucleoside independently selected from the group consisting of2′-O-alkyl-RNA, 2′-O-methyl-RNA (2′oMe), 2′-alkoxy-RNA,2′-O-methoxyethyl-RNA (2′MOE), 2′-amino-DNA, 2′-fluoro-DNA, arabinonucleic acid (ANA), 2′-fluoro-ANA and LNA nucleosides. It isadvantageous if one or more of the modified nucleoside(s) is a lockednucleic acid (LNA).

In a further embodiment the antisense oligonucleotide progranulinagonist comprises at least one modified internucleoside linkage.Suitable internucleoside modifications are described in the“Definitions” section under “Modified internucleoside linkage”. It isadvantageous if at least 75%, such as all, the internucleoside linkageswithin the contiguous nucleotide sequence are phosphorothioate orboranophosphate internucleoside linkages. In some embodiments all theinternucleotide linkages in the contiguous sequence of theoligonucleotide are phosphorothioate linkages.

An antisense oligonucleotide progranulin agonist may have the structure:

The invention also includes an antisense oligonucleotide progranulinagonist wherein the oligonucleotide is the oligonucleotide compoundTgGccAggGatCagGG (SEQ ID NO: 106) wherein capital letters representbeta-D-oxy LNA nucleosides, lowercase letters represent DNA nucleosides,all LNA C are 5-methyl cytosine, and all internucleoside linkages arephosphorothioate internucleoside linkages.

Numbered Paragraphs of the Invention

Aspects of the present invention will now be described by way ofnumbered paragraphs.

1. An antisense oligonucleotide progranulin agonist, wherein theantisense oligonucleotide is 8-40 nucleotides in length and comprises acontiguous nucleotide sequence of 8-40 nucleotides in length which arefully complementary to a human progranulin pre-mRNA or mRNA transcript,such as SEQ ID NO 1.

2. The antisense oligonucleotide according to paragraph 1, wherein thecontiguous nucleotide sequence is of a length of at least 12 nucleotidesin length, such as 12-16 or 12-18 nucleotides in length.

3. The antisense oligonucleotide according to paragraph 1 or 2, whereinthe contiguous nucleotide sequence is the same length as the antisenseoligonucleotide.

4. The antisense oligonucleotide according to any one of paragraphs 1-3,wherein contiguous nucleotide sequence is fully complementary to SEQ IDNO 2, SEQ ID NO 689, SEQ ID NO 683, SEQ ID NO 684, SEQ ID NO 685, SEQ IDNO 686, SEQ ID NO 687, SEQ ID NO 688, or a sequence selected from thegroup consisting of SEQ ID NO 343-682.

5. The antisense oligonucleotide according to any one of paragraphs 1-4,wherein contiguous nucleotide sequence is fully complementary to a 5′UTRregion of a human progranulin mRNA transcript.

6. The antisense oligonucleotide according to any one of paragraphs 1-5,wherein contiguous nucleotide sequence is fully complementary tonucleotides 38-246 of SEQ ID NO 1.

7. The antisense oligonucleotide according to any one of paragraphs 1-6,wherein contiguous nucleotide sequence is fully complementary to SEQ IDNO 2, or SEQ ID NO 689.

8. The antisense oligonucleotide according to any one of paragraphs 1-7,wherein the contiguous nucleotide sequence is fully complementary to asequence selected from the group consisting of SEQ ID NO 568, 571, 575,576, 577, 578, 584 & 586.

9. The antisense oligonucleotide according to any one of paragraphs 1-4,wherein contiguous nucleotide sequence is fully complementary to a 3′UTRregion of a human progranulin mRNA transcript.

10. The antisense oligonucleotide according to any one of paragraphs 1-4or 9, wherein contiguous nucleotide sequence is fully complementary tonucleotides 2039-2346 of SEQ ID NO 1.

11. The antisense oligonucleotide according to any one of paragraphs1-4, 9 or 10 wherein contiguous nucleotide sequence is fullycomplementary to a sequence selected from the group consisting of SEQ IDNO 684, 685, 683, 686, 687, and 688.

12. The antisense oligonucleotide according to any one of paragraphs1-4, 9, 10, or 11 wherein contiguous nucleotide sequence is fullycomplementary to a sequence selected from the group consisting of SEQ IDNOs 607, 608, 609, 610, 611, 612, 619, 620, 633, 640, 641, 645, 651, and652.

13. The antisense oligonucleotide according to any one of paragraphs1-12, wherein contiguous nucleotide sequence is a sequence selected fromthe group consisting of SEQ ID NO 3-342, or at least 8 or at least 10contiguous nucleotides thereof.

14. The antisense oligonucleotide according to any one of paragraphs1-13, wherein the oligonucleotide is or comprises an antisenseoligonucleotide mixmer or totalmer.

15. The antisense oligonucleotide of any one of paragraphs 1-14, whereinthe antisense oligonucleotide or contiguous nucleotide sequence thereofis 10-20 nucleotides in length.

16. The antisense oligonucleotide according to paragraph 1, wherein theantisense oligonucleotide is selected from the group consisting of COMPID NOs 3-342.

17. A conjugate comprising the antisense oligonucleotide according toany one of paragraphs 1-16, and at least one conjugate moiety covalentlyattached to said oligonucleotide.

18. A pharmaceutically acceptable salt of the antisense oligonucleotideaccording to any one of paragraphs 1-16, or the conjugate according toparagraph 17.

19. The pharmaceutically acceptable salt of paragraph 18, wherein thesalt is a sodium salt or a potassium salt.

20. A pharmaceutical composition comprising the antisenseoligonucleotide of paragraph 1-16 or the conjugate of paragraph 17 and apharmaceutically acceptable diluent, solvent, carrier, salt and/oradjuvant.

21. A pharmaceutical composition according to paragraph 20, wherein thepharmaceutical composition comprises the antisense oligonucleotide ofparagraph 1-16 or the conjugate of paragraph 17, or the pharmaceuticallyacceptable salt of paragraph 18 or 19 and an aqueous diluent or solvent,such as phosphate buffered saline.

22. An in vivo or in vitro method for enhancing the expression ofprogranulin in a cell which is expressing progranulin, said methodcomprising administering an antisense oligonucleotide of any one ofparagraphs 1-16 or the conjugate according to paragraph 17, or the saltaccording to paragraph 18 or 19, or the pharmaceutical compositionaccording to paragraph 20 or 21 in an effective amount to said cell.

23. The method according to paragraph 22, wherein the cell is either ahuman cell or a mammalian cell.

24. A method for treating or preventing neurological disease comprisingadministering a therapeutically or prophylactically effective amount ofan antisense oligonucleotide of any one of paragraphs 1-16 or theconjugate according to paragraph 17, or the salt according to paragraph18 or 19, or the pharmaceutical composition according to paragraph 20 or21 to a subject suffering from or susceptible to neurological disease.

25. The antisense oligonucleotide of any one of paragraphs 1-16 or theconjugate according to paragraph 17, or the salt according to paragraph18 or 19, or the pharmaceutical composition according to paragraph 20 or21 for use as a medicament.

26. The an antisense oligonucleotide of any one of paragraphs 1-16 orthe conjugate according to paragraph 17, or the salt according toparagraph 18 or 19, or the pharmaceutical composition according toparagraph 20 or 21 for use in the treatment of a neurological disease,such as a TDP-43 pathology.

27. The an antisense oligonucleotide of any one of paragraphs 1-16 orthe conjugate according to paragraph 17, or the salt according toparagraph 18 or 19, or the pharmaceutical composition according toparagraph 20 or 21 for use in the treatment of progranulinhaploinsufficiency.

28. Use of the antisense oligonucleotide of paragraph 1-16 or theconjugate according to paragraph 17, or the salt according to paragraph18 or 19, or the pharmaceutical composition according to paragraph 20 or21 for the preparation of a medicament for treatment or prevention of aneurological disease, such as a TDP-43 pathology.

29. Use of the antisense oligonucleotide of paragraph 1-16 or theconjugate according to paragraph 17, or the salt according to paragraph18 or 19, or the pharmaceutical composition according to paragraph 20 or21, for the preparation of a medicament for treatment of progranulinhaploinsufficiency.

30. The method or use according to any one of paragraphs 22-29, whereinthe method or use is for the treatment of fronto temporal dementia(FTD), neuropathologic frontotemporal lobar degeneration orneuroinflammation.

NUMBERED EMBODIMENTS OF THE INVENTION

Numbered embodiments of the present invention will now be described.

1. An antisense oligonucleotide progranulin agonist, wherein theantisense oligonucleotide is 8-40 nucleotides in length and comprises acontiguous nucleotide sequence of 8-40 nucleotides in length which arecomplementary to a human progranulin pre-mRNA or mRNA transcript.

2. The antisense oligonucleotide progranulin agonist according toembodiment 1, wherein the contiguous nucleotide sequence is of a lengthof at least 12 nucleotides in length.

3. The antisense oligonucleotide progranulin agonist according toembodiment 1 or embodiment 2, wherein the contiguous nucleotide sequenceis the same length as the antisense oligonucleotide.

4. The antisense oligonucleotide progranulin agonist according to anyone of embodiments 1-3, wherein the contiguous nucleotide sequence iscomplementary to a 5′UTR region of a human progranulin mRNA transcript.

5. The antisense oligonucleotide progranulin agonist according toembodiment 4, wherein the contiguous nucleotide sequence iscomplementary to SEQ ID NO 2, SEQ ID NO 689, SEQ ID NO 683, or asequence selected from the group consisting of SEQ ID NO 343-586.

6. The antisense oligonucleotide progranulin agonist according to anyone of embodiments 1-5, wherein the contiguous nucleotide sequence isselected from SEQ ID NO 105, SEQ ID NO 106, SEQ ID NO 110, SEQ ID NO113, SEQ ID NO 114, SEQ ID NO 231 and SEQ ID NO 241 or at least 8 or atleast 10 contiguous nucleotides thereof.

7. The antisense oligonucleotide progranulin agonist according to anyone of embodiments 1-3, wherein contiguous nucleotide sequence iscomplementary to a 3′UTR region of a human progranulin mRNA transcript.

8. The antisense oligonucleotide progranulin agonist according toembodiment 7, wherein the contiguous nucleotide sequence iscomplementary to SEQ ID NO 684, SEQ ID NO 685, SEQ ID NO 686, SEQ ID NO687, SEQ ID NO 688, or a sequence selected from the group consisting ofSEQ ID NO 587-682.

9. The antisense oligonucleotide progranulin agonist according to anyone of embodiments 1-8, wherein the antisense oligonucleotideprogranulin agonist is or comprises an antisense oligonucleotide mixmeror totalmer.

10. An antisense oligonucleotide progranulin agonist having thestructure:

11. An antisense oligonucleotide progranulin agonist wherein theoligonucleotide is the oligonucleotide compound TgGccAggGatCagGG (SEQ IDNO: 106) wherein capital letters represent beta-D-oxy LNA nucleosides,lowercase letters represent DNA nucleosides, all LNA C are 5-methylcytosine, and all internucleoside linkages are phosphorothioateinternucleoside linkages.

12. An in vivo or in vitro method for enhancing the expression ofprogranulin in a cell which is expressing progranulin, said methodcomprising administering an antisense oligonucleotide progranulinagonist according to any one of embodiments 1-11 in an effective amountto said cell.

13. The antisense oligonucleotide progranulin agonist according to anyone of embodiments 1-11, for use in the treatment of a neurologicaldisease.

14. The antisense oligonucleotide progranulin agonist or pharmaceuticalcomposition for use in the treatment of a neurological disease accordingto embodiment 13, wherein the neurological disease is a TDP-43pathology.

15. The antisense oligonucleotide progranulin agonist according to anyone of embodiments 1-11 for use in the treatment of progranulinhaploinsufficiency.

EXAMPLES Example 1

GRN 5′ UTR Luciferase Reporter Constructs

The GRN 5′ UTR sequence (SEQ ID #690) was cloned into the psiCHECK2plasmid (Promega) immediately in front of the renilla luciferase ATGsite using the Q5 site-directed mutagenesis kit (New England Biolabs)according to manufactorer's instruction.

5′ UTR sequence from nucleotide number 38 to 256 according to Homosapiens granulin precursor (GRN), RefSeq NM_002087.3 (SEQ ID NO 1):

SEQ 690 ID#GGCGAGAGGAAGCAGGGAGGAGAGTGATTTGAGTAGAAAAGAAACACAGCATTCCAGGCTGGCCCCACCTCTATATTGATAAGTAGCCAATGGGAGCGGGTAGCCCTGATCCCTGGCCAATGGAAACTGAGGTAGGCGGGTCATCGCGCTGGGGTCTGTAGTCTGAGCGCTACCCGGTTGCTGCTGCCCAAGGACCGCGGAGTCGGACGCAGGCAGACC

For the site-directed mutagenesis and insertion of the GRN 5′ UTR thefollowing primers were used:

Forward primer SEQ ID NO 6915′-ATGGAAACTGAGGTAGGCGGGTCATCGCGCTGGGGTCTGTAGTCTGAGCGCTACCCGGTTGCTGCTGCCCAAGGACCGCGGAGTCGGACGCAGGCAGACCATGGCTTCCAAGGTGTACGACCCCGAGC-3′ and reverse primer SEQ ID NO 6925′-TGGCCAGGGATCAGGGCTACCCGCTCCCATTGGCTACTTATCAATATAGAGGTGGGGCCAGCCTGGAATGCTGTGTTTCTTTTCTACTCAAATCACTCTCCTCCCTGCTTCCTCTCGCCGGCTAGCCTATAGTGAGTCGTATTA AGTAC

After transformation of chemical competent bacteria (One Shot TOP10Chemically Competent E. coli, Thermofisher) and overnight growth on LBagar plates containing ampicillin (imMedia Growth Medium, agar,ampicillin, Thermofisher), single colonies were selected and furthergrown overnight with constant shaking at 37 Degrees Celcius in LB brothmedium containing ampicillin (50 μg/mL) (Thermofisher). Final mini- andmidi-prep plasmid purifications were done according to vendorsinstruction (Qiagen). The inserted 5′ UTR GRN sequences were verifiedusing Sanger sequencing (Eurofins Genomics, Ebersberg, Germany).

Example 2

GRN 3′ UTR Luciferase Reporter Constructs

The GRN 3′ UTR (SEQ ID #2) was cloned into the psiCHECK2 plasmid(Promega) after the renilla luciferase coding sequence using thepsiCHECK2 multiple cloning site and the XhoI and NotI restriction sites.

3′ UTR sequence from nucleotide number 2039 to 2346 according to Homosapiens granulin precursor (GRN), RefSeq NM_002087.3 (SEQ ID NO 1).

SEQ ID#2: GGGACAGTACTGAAGACTCTGCAGCCCTCGGGACCCCACTCGGAGGGTGCCCTCTGCTCAGGCCTCCCTAGCACCTCCCCCTAACCAAATTCTCCCTGGACCCCATTCTGAGCTCCCCATCACCATGGGAGGTGGGGCCTCAATCTAAGGCCTTCCCTGTCAGAAGGGGGTTGTGGCAAAAGCCACATTACAAGCTGCCATCCCCTCCCCGTTTCAGTGGACCCTGTGGCCAGGTGCTTTTCCCTATCCACAGGGGTGTTTGTGTGTGTGCGCGTGTGCGTTTCAATAAAGTTT GTACACTTTCTTAA

Double stranded DNA fragment (gBlock, Integrated DNA technologies)containing the GRN 3′ UTR (SEQ ID #2) flanked by XhoI and NotI sites wascut by XhoI and NotI enzymes (New England Biolabs) according to vendorsprotocol and ligated using T4 Ligase (New England Biolabs) into thepreviously XhoI/NotI cut psiCHECK2 plasmid.

After transformation of chemical competent bacteria (One Shot® TOP10Chemically Competent E. coli, Thermofisher) and overnight growth on LBagar plates containing ampicillin (imMedia Growth Medium, agar,ampicilin, Thermofisher), single colonies were selected and furthergrown overnight with constant shaking at 37 Degrees Celcius in LB brothmedium containing ampicillin (50 μg/mL) (Thermofisher). Final mini- andmidiprep plasmid purifications were done according to vendorsinstruction (Qiagen). The inserted 3′ UTR GRN sequence was verifiedusing Sanger sequencing (Eurofins Genomics, Ebersberg, Germany).

Example 3 Luciferase Reporter Assays

The day before transfection, 15000 HeLa cells per well were seeded in96-well plates (Nunc™ F96 MicroWell™ White Polystyrene Plates) in 100 μLfull growth medium. The day at transfection, media is removed and thetransfection mixture consisting of 80 μL Opti-MEM Reduced Serum Medium(ThermoFisher Scientific), 6.25 μg/mL Lipofectamine 2000 (ThermoFisherScientific) and 100 ng psiCHECK2 plasmid with 5′ UTR/3′UTR of GRN isadded to each well according to manufactorer's instructions(ThermoFisher Scientific). Shortly after, 20 μL of Opti-MEM ReducedSerum Medium with 500 nM of each antisense oligonucleotide is added toeach well for a final concentration of 100 nM. Wells with seeded cellsnot exposed to transfection reagents are included to correct forbackground luciferase activity. After 6 hours incubation, transfectionmixture is removed from all wells and replaced with full growth medium.The following day, media is removed and replaced with 75 μL PBS, and theFirefly luciferase activity is measured using the Dual-GLo luciferasesystem (Promega) according to vendors protocol and the EnSightMultimode. Plate Reader (Perkin Elmer). Measurement of The fireflyluciferase activity is followed by measurement of the renilla luciferaseactivity. After correction of the background luciferase activity foreach well, the relative luciferase activity is calculated by dividingthe Renilla luciferase activity by the firefly luciferase activity foreach well to correct for transfection efficiency. Finally, for eachantisense oligonucleotides the relative luciferase activity isnormalized to PBS transfected cells (PBS=1) and values >1 reflects thatthe respective antisense oligonucleotides have increased theactivity/expression of the renilla luciferase activity.

Example 4

Antisense oligonucleotides were designed for the 5′ UTR from position 38to 241 according to RefSeq NM_002087.3 (SEQ ID NO 1) with one nucleotidebasepair shift as shown in table 1, which also provides the data fromthe luciferase assay, were a value of greater than 1 indicates anincreased expression of progranulin (i.e. progranulin agonist activityof the antisense oligonucleotide), and a value lower than 1 indicates adecreased expression of progranulin (i.e. an inhibition or antagonisticeffect, on progranulin expression).

TABLE 1All the antisense oligonucleotides are designed as 16-mers DNA-LNA mixmers with a phosphorothioatebackbone, LNA at the very 5′ and 3′ position and e.g. LNA for every 2^(nd) or 3^(rd) nucleotide (seeCompound table). RefSeq Relative Oligonucleotide NM_002087.3 Targetluciferase Compound ID Sequence Motif (SEQ ID NO 1) Site activity(See Compound (nucleobase Start End Sequence Target (Relative SEQ IDTable) Sequence) Position Position ID Site Sequence to PBS) SEQ ID 3COMP ID 3 CCTGCTTCCTCTCGCC 38 53 SEQ ID GGCGAGAGGAAGCAGG 0,47 343SEQ ID 4 COMP ID 4 CCCTGCTTCCTCTCGC 39 54 SEQ ID GCGAGAGGAAGCAGGG 0,60344 SEQ ID 5 COMP ID 5 TCCCTGCTTCCTCTCG 40 55 SEQ ID CGAGAGGAAGCAGGGA0,62 345 SEQ ID 6 COMP ID 6 CTCCCTGCTTCCTCTC 41 56 SEQ IDGAGAGGAAGCAGGGAG 0,65 346 SEQ ID 7 COMP ID 7 CCTCCCTGCTTCCTCT 42 57SEQ ID AGAGGAAGCAGGGAGG 0,85 347 SEQ ID 8 COMP ID 8 TCCTCCCTGCTTCCTC 4358 SEQ ID GAGGAAGCAGGGAGGA 0,81 348 SEQ ID 9 COMP ID 9 CTCCTCCCTGCTTCCT44 59 SEQ ID AGGAAGCAGGGAGGAG 0,53 349 SEQ ID 10 COMP ID 10TCTCCTCCCTGCTTCC 45 60 SEQ ID GGAAGCAGGGAGGAGA 0,80 350 SEQ ID 11COMP ID 11 CTCTCCTCCCTGCTTC 46 61 SEQ ID GAAGCAGGGAGGAGAG 0,78 351SEQ ID 12 COMP ID 12 ACTCTCCTCCCTGCTT 47 62 SEQ ID AAGCAGGGAGGAGAGT 0,78352 SEQ ID 13 COMP ID 13 CACTCTCCTCCCTGCT 48 63 SEQ ID AGCAGGGAGGAGAGTG0,53 353 SEQ ID 14 COMP ID 14 TCACTCTCCTCCCTGC 49 64 SEQ IDGCAGGGAGGAGAGTGA 0,66 354 SEQ ID 15 COMP ID 15 ATCACTCTCCTCCCTG 50 65SEQ ID CAGGGAGGAGAGTGAT n.d. 355 SEQ ID 16 COMP ID 16 AATCACTCTCCTCCCT51 66 SEQ ID AGGGAGGAGAGTGATT n.d. 356 SEQ ID 17 COMP ID 17AAATCACTCTCCTCCC 52 67 SEQ ID GGGAGGAGAGTGATTT n.d. 357 SEQ ID 18COMP ID 18 CAAATCACTCTCCTCC 53 68 SEQ ID GGAGGAGAGTGATTTG n.d. 358SEQ ID 19 COMP ID 19 TCAAATCACTCTCCTC 54 69 SEQ ID GAGGAGAGTGATTTGA 0,56359 SEQ ID 20 COMP ID 20 CTCAAATCACTCTCCT 55 70 SEQ ID AGGAGAGTGATTTGAG0,58 360 SEQ ID 21 COMP ID 21 ACTCAAATCACTCTCC 56 71 SEQ IDGGAGAGTGATTTGAGT 0,50 361 SEQ ID 22 COMP ID 22 TACTCAAATCACTCTC 57 72SEQ ID GAGAGTGATTTGAGTA 0,44 362 SEQ ID 23 COMP ID 23 CTACTCAAATCACTCT58 73 SEQ ID AGAGTGATTTGAGTAG 0,61 363 SEQ ID 24 COMP ID 24TCTACTCAAATCACTC 59 74 SEQ ID GAGTGATTTGAGTAGA 0,44 364 SEQ ID 25COMP ID 25 TTCTACTCAAATCACT 60 75 SEQ ID AGTGATTTGAGTAGAA 0,47 365SEQ ID 26 COMP ID 26 TTTCTACTCAAATCAC 61 76 SEQ ID GTGATTTGAGTAGAAA 0,57366 SEQ ID 27 COMP ID 27 TTTTCTACTCAAATCA 62 77 SEQ ID TGATTTGAGTAGAAAA0,49 367 SEQ ID 28 COMP ID 28 CTTTTCTACTCAAATC 63 78 SEQ IDGATTTGAGTAGAAAAG 0,54 368 SEQ ID 29 COMP ID 29 TCTTTTCTACTCAAAT 64 79SEQ ID ATTTGAGTAGAAAAGA 0,49 369 SEQ ID 30 COMP ID 30 TTCTTTTCTACTCAAA65 80 SEQ ID TTTGAGTAGAAAAGAA 0,38 370 SEQ ID 31 COMP ID 31TTTCTTTTCTACTCAA 66 81 SEQ ID TTGAGTAGAAAAGAAA 0,59 371 SEQ ID 32COMP ID 32 GTTTCTTTTCTACTCA 67 82 SEQ ID TGAGTAGAAAAGAAAC 0,44 372SEQ ID 33 COMP ID 33 TGTTTCTTTTCTACTC 68 83 SEQ ID GAGTAGAAAAGAAACA 0,61373 SEQ ID 34 COMP ID 34 GTGTTTCTTTTCTACT 69 84 SEQ ID AGTAGAAAAGAAACAC0,56 374 SEQ ID 35 COMP ID 35 TGTGTTTCTTTTCTAC 70 85 SEQ IDGTAGAAAAGAAACACA 0,47 375 SEQ ID 36 COMP ID 36 CTGTGTTTCTTTTCTA 71 86SEQ ID TAGAAAAGAAACACAG 0,36 376 SEQ ID 37 COMP ID 37 GCTGTGTTTCTTTTCT72 87 SEQ ID AGAAAAGAAACACAGC 0,45 377 SEQ ID 38 COMP ID 38TGCTGTGTTTCTTTTC 73 88 SEQ ID GAAAAGAAACACAGCA 0,58 378 SEQ ID 39COMP ID 39 ATGCTGTGTTTCTTTT 74 89 SEQ ID AAAAGAAACACAGCAT 0,77 379SEQ ID 40 COMP ID 40 AATGCTGTGTTTCTTT 75 90 SEQ ID AAAGAAACACAGCATT 0,53380 SEQ ID 41 COMP ID 41 GAATGCTGTGTTTCTT 76 91 SEQ ID AAGAAACACAGCATTC0,73 381 SEQ ID 42 COMP ID 42 GGAATGCTGTGTTTCT 77 92 SEQ IDAGAAACACAGCATTCC 0,77 382 SEQ ID 43 COMP ID 43 TGGAATGCTGTGTTTC 78 93SEQ ID GAAACACAGCATTCCA 0,69 383 SEQ ID 44 COMP ID 44 CTGGAATGCTGTGTTT79 94 SEQ ID AAACACAGCATTCCAG 0,63 384 SEQ ID 45 COMP ID 45CCTGGAATGCTGTGTT 80 95 SEQ ID AACACAGCATTCCAGG 0,58 385 SEQ ID 46COMP ID 46 GCCTGGAATGCTGTGT 81 96 SEQ ID ACACAGCATTCCAGGC 0,57 386SEQ ID 47 COMP ID 47 AGCCTGGAATGCTGTG 82 97 SEQ ID CACAGCATTCCAGGCT 0,48387 SEQ ID 48 COMP ID 48 CAGCCTGGAATGCTGT 83 98 SEQ ID ACAGCATTCCAGGCTG0,62 388 SEQ ID 49 COMP ID 49 CCAGCCTGGAATGCTG 84 99 SEQ IDCAGCATTCCAGGCTGG 0,40 389 SEQ ID 50 COMP ID 50 GCCAGCCTGGAATGCT 85 100SEQ ID AGCATTCCAGGCTGGC 0,32 390 SEQ ID 51 COMP ID 51 GGCCAGCCTGGAATGC86 101 SEQ ID GCATTCCAGGCTGGCC 0,24 391 SEQ ID 52 COMP ID 52GGGCCAGCCTGGAATG 87 102 SEQ ID CATTCCAGGCTGGCCC 0,15 392 SEQ ID 53COMP ID 53 GGGGCCAGCCTGGAAT 88 103 SEQ ID ATTCCAGGCTGGCCCC 0,20 393SEQ ID 54 COMP ID 54 TGGGGCCAGCCTGGAA 104 SEQ ID TTCCAGGCTGGCCCCA 0,62394 SEQ ID 55 COMP ID 55 GTGGGGCCAGCCTGGA 90 105 SEQ ID TCCAGGCTGGCCCCAC0,54 395 SEQ ID 56 COMP ID 56 GGTGGGGCCAGCCTGG 91 106 SEQ IDCCAGGCTGGCCCCACC 0,62 396 SEQ ID 57 COMP ID 57 AGGTGGGGCCAGCCTG 92 107SEQ ID CAGGCTGGCCCCACCT 0,38 397 SEQ ID 58 COMP ID 58 GAGGTGGGGCCAGCCT93 108 SEQ ID AGGCTGGCCCCACCTC 0,46 398 SEQ ID 59 COMP ID 59AGAGGTGGGGCCAGCC 94 109 SEQ ID GGCTGGCCCCACCTCT 0,32 399 SEQ ID 60COMP ID 60 TAGAGGTGGGGCCAGC 95 110 SEQ ID GCTGGCCCCACCTCTA 0,53 400SEQ ID 61 COMP ID 61 ATAGAGGTGGGGCCAG 96 111 SEQ ID CTGGCCCCACCTCTAT0,37 401 SEQ ID 62 COMP ID 62 TATAGAGGTGGGGCCA 97 112 SEQ IDTGGCCCCACCTCTATA 0,68 402 SEQ ID 63 COMP ID 63 ATATAGAGGTGGGGCC 98 113SEQ ID GGCCCCACCTCTATAT 0,65 403 SEQ ID 64 COMP ID 64 AATATAGAGGTGGGGC99 114 SEQ ID GCCCCACCTCTATATT 0,61 404 SEQ ID 65 COMP ID 65CAATATAGAGGTGGGG 100 115 SEQ ID CCCCACCTCTATATTG 0,79 405 SEQ ID 66COMP ID 66 TCAATATAGAGGTGGG 101 116 SEQ ID CCCACCTCTATATTGA 0,86 406SEQ ID 67 COMP ID 67 ATCAATATAGAGGTGG 102 117 SEQ ID CCACCTCTATATTGAT0,80 407 SEQ ID 68 COMP ID 68 TATCAATATAGAGGTG 103 118 SEQ IDCACCTCTATATTGATA 0,65 408 SEQ ID 69 COMP ID 69 TTATCAATATAGAGGT 104 119SEQ ID ACCTCTATATTGATAA 0,49 409 SEQ ID 70 COMP ID 70 CTTATCAATATAGAGG105 120 SEQ ID CCTCTATATTGATAAG 0,93 410 SEQ ID 71 COMP ID 71ACTTATCAATATAGAG 106 121 SEQ ID CTCTATATTGATAAGT 0,73 411 SEQ ID 72COMP ID 72 TACTTATCAATATAGA 107 122 SEQ ID TCTATATTGATAAGTA 0,87 412SEQ ID 73 COMP ID 73 CTACTTATCAATATAG 108 123 SEQ ID CTATATTGATAAGTAG0,83 413 SEQ ID 74 COMP ID 74 GCTACTTATCAATATA 109 124 SEQ IDTATATTGATAAGTAGC 0,64 414 SEQ ID 75 COMP ID 75 GGCTACTTATCAATAT 110 125SEQ ID ATATTGATAAGTAGCC 0,71 415 SEQ ID 76 COMP ID 76 TGGCTACTTATCAATA111 126 SEQ ID TATTGATAAGTAGCCA 0,81 416 SEQ ID 77 COMP ID 77TTGGCTACTTATCAAT 112 127 SEQ ID ATTGATAAGTAGCCAA 0,48 417 SEQ ID 78COMP ID 78 ATTGGCTACTTATCAA 113 128 SEQ ID TTGATAAGTAGCCAAT 0,88 418SEQ ID 79 COMP ID 79 CATTGGCTACTTATCA 114 129 SEQ ID TGATAAGTAGCCAATG0,72 419 SEQ ID 80 COMP ID 80 CCATTGGCTACTTATC 115 130 SEQ IDGATAAGTAGCCAATGG 0,53 420 SEQ ID 81 COMP ID 81 CCCATTGGCTACTTAT 116 131SEQ ID ATAAGTAGCCAATGGG 0,63 421 SEQ ID 82 COMP ID 82 TCCCATTGGCTACTTA117 132 SEQ ID TAAGTAGCCAATGGGA 0,53 422 SEQ ID 83 COMP ID 83CTCCCATTGGCTACTT 118 133 SEQ ID AAGTAGCCAATGGGAG 0,57 423 SEQ ID 84COMP ID 84 GCTCCCATTGGCTACT 119 134 SEQ ID AGTAGCCAATGGGAGC 0,52 424SEQ ID 85 COMP ID 85 CGCTCCCATTGGCTAC 120 135 SEQ ID GTAGCCAATGGGAGCG0,25 425 SEQ ID 86 COMP ID 86 CCGCTCCCATTGGCTA 121 136 SEQ IDTAGCCAATGGGAGCGG 0,37 426 SEQ ID 87 COMP ID 87 CCCGCTCCCATTGGCT 122 137SEQ ID AGCCAATGGGAGCGGG 0,28 427 SEQ ID 88 COMP ID 88 ACCCGCTCCCATTGGC123 138 SEQ ID GCCAATGGGAGCGGGT 0,30 428 SEQ ID 89 COMP ID 89TACCCGCTCCCATTGG 124 139 SEQ ID CCAATGGGAGCGGGTA 0,43 429 SEQ ID 90COMP ID 90 CTACCCGCTCCCATTG 125 140 SEQ ID CAATGGGAGCGGGTAG 0,38 430SEQ ID 91 COMP ID 91 GCTACCCGCTCCCATT 126 141 SEQ ID AATGGGAGCGGGTAGC0,65 431 SEQ ID 92 COMP ID 92 GGCTACCCGCTCCCAT 127 142 SEQ IDATGGGAGCGGGTAGCC 0,51 432 SEQ ID 93 COMP ID 93 GGGCTACCCGCTCCCA 128 143SEQ ID TGGGAGCGGGTAGCCC 0,38 433 SEQ ID 94 COMP ID 94 AGGGCTACCCGCTCCC129 144 SEQ ID GGGAGCGGGTAGCCCT 0,50 434 SEQ ID 95 COMP ID 95CAGGGCTACCCGCTCC 130 145 SEQ ID GGAGCGGGTAGCCCTG 0,45 435 SEQ ID 96COMP ID 96 TCAGGGCTACCCGCTC 131 146 SEQ ID GAGCGGGTAGCCCTGA 0,50 436SEQ ID 97 COMP ID 97 ATCAGGGCTACCCGCT 132 147 SEQ ID AGCGGGTAGCCCTGAT0,39 437 SEQ ID 98 COMP ID 98 GATCAGGGCTACCCGC 133 148 SEQ IDGCGGGTAGCCCTGATC 0,31 438 SEQ ID 99 COMP ID 99 GGATCAGGGCTACCCG 134 149SEQ ID CGGGTAGCCCTGATCC 0,32 439 SEQ ID 100 COMP ID 100 GGGATCAGGGCTACCC135 150 SEQ ID GGGTAGCCCTGATCCC 0,56 440 SEQ ID 101 COMP ID 101AGGGATCAGGGCTACC 136 151 SEQ ID GGTAGCCCTGATCCCT 0,41 441 SEQ ID 102COMP ID 102 CAGGGATCAGGGCTAC 137 152 SEQ ID GTAGCCCTGATCCCTG 0,86 442SEQ ID 103 COMP ID 103 CCAGGGATCAGGGCTA 138 153 SEQ ID TAGCCCTGATCCCTGG0,65 443 SEQ ID 104 COMP ID 104 GCCAGGGATCAGGGCT 139 154 SEQ IDAGCCCTGATCCCTGGC 0,65 444 SEQ ID 105 COMP ID 105 GGCCAGGGATCAGGGC 140155 SEQ ID GCCCTGATCCCTGGCC 1,00 445 SEQ ID 106 COMP ID 106TGGCCAGGGATCAGGG 141 156 SEQ ID CCCTGATCCCTGGCCA 1,07 446 SEQ ID 107COMP ID 107 TTGGCCAGGGATCAGG 142 157 SEQ ID CCTGATCCCTGGCCAA 0,52 447SEQ ID 108 COMP ID 108 ATTGGCCAGGGATCAG 143 158 SEQ ID CTGATCCCTGGCCAAT0,86 448 SEQ ID 109 COMP ID 109 CATTGGCCAGGGATCA 144 159 SEQ IDTGATCCCTGGCCAATG 0,67 449 SEQ ID 110 COMP ID 110 CCATTGGCCAGGGATC 145160 SEQ ID GATCCCTGGCCAATGG 0,54 450 SEQ ID 111 COMP ID 111TCCATTGGCCAGGGAT 146 161 SEQ ID ATCCCTGGCCAATGGA n.d. 451 SEQ ID 112COMP ID 112 TTCCATTGGCCAGGGA 147 162 SEQ ID TCCCTGGCCAATGGAA n.d. 452SEQ ID 113 COMP ID 113 TTTCCATTGGCCAGGG 148 163 SEQ ID CCCTGGCCAATGGAAAn.d. 453 SEQ ID 114 COMP ID 114 GTTTCCATTGGCCAGG 149 164 SEQ IDCCTGGCCAATGGAAAC n.d. 454 SEQ ID 115 COMP ID 115 AGTTTCCATTGGCCAG 150165 SEQ ID CTGGCCAATGGAAACT 0,43 455 SEQ ID 116 COMP ID 116CAGTTTCCATTGGCCA 151 166 SEQ ID TGGCCAATGGAAACTG 0,56 456 SEQ ID 117COMP ID 117 TCAGTTTCCATTGGCC 152 167 SEQ ID GGCCAATGGAAACTGA 0,61 457SEQ ID 118 COMP ID 118 CTCAGTTTCCATTGGC 153 168 SEQ ID GCCAATGGAAACTGAG0,71 458 SEQ ID 119 COMP ID 119 CCTCAGTTTCCATTGG 154 169 SEQ IDCCAATGGAAACTGAGG 1,03 459 SEQ ID 120 COMP ID 120 ACCTCAGTTTCCATTG 155170 SEQ ID CAATGGAAACTGAGGT 0,90 460 SEQ ID 121 COMP ID 121TACCTCAGTTTCCATT 156 171 SEQ ID AATGGAAACTGAGGTA 0,95 461 SEQ ID 122COMP ID 122 CTACCTCAGTTTCCAT 157 172 SEQ ID ATGGAAACTGAGGTAG 0,63 462SEQ ID 123 COMP ID 123 CCTACCTCAGTTTCCA 158 173 SEQ ID TGGAAACTGAGGTAGG0,62 463 SEQ ID 124 COMP ID 124 GCCTACCTCAGTTTCC 159 174 SEQ IDGGAAACTGAGGTAGGC 0,49 464 SEQ ID 125 COMP ID 125 CGCCTACCTCAGTTTC 160175 SEQ ID GAAACTGAGGTAGGCG 1,18 465 SEQ ID 126 COMP ID 126CCGCCTACCTCAGTTT 161 176 SEQ ID AAACTGAGGTAGGCGG 0,55 466 SEQ ID 127COMP ID 127 CCCGCCTACCTCAGTT 162 177 SEQ ID AACTGAGGTAGGCGGG 0,72 467SEQ ID 128 COMP ID 128 ACCCGCCTACCTCAGT 163 178 SEQ ID ACTGAGGTAGGCGGGT0,44 468 SEQ ID 129 COMP ID 129 GACCCGCCTACCTCAG 164 179 SEQ IDCTGAGGTAGGCGGGTC 0,42 469 SEQ ID 130 COMP ID 130 TGACCCGCCTACCTCA 165180 SEQ ID TGAGGTAGGCGGGTCA 0,28 470 SEQ ID 131 COMP ID 131ATGACCCGCCTACCTC 166 181 SEQ ID GAGGTAGGCGGGTCAT 0,19 471 SEQ ID 132COMP ID 132 GATGACCCGCCTACCT 167 182 SEQ ID AGGTAGGCGGGTCATC 0,18 472SEQ ID 133 COMP ID 133 CGATGACCCGCCTACC 168 183 SEQ ID GGTAGGCGGGTCATCG0,34 473 SEQ ID 134 COMP ID 134 GCGATGACCCGCCTAC 169 184 SEQ IDGTAGGCGGGTCATCGC 0,73 474 SEQ ID 135 COMP ID 135 CGCGATGACCCGCCTA 170185 SEQ ID TAGGCGGGTCATCGCG 0,66 475 SEQ ID 136 COMP ID 136GCGCGATGACCCGCCT 171 186 SEQ ID AGGCGGGTCATCGCGC 0,46 476 SEQ ID 137COMP ID 137 AGCGCGATGACCCGCC 172 187 SEQ ID GGCGGGTCATCGCGCT 0,46 477SEQ ID 138 COMP ID 138 CAGCGCGATGACCCGC 173 188 SEQ ID GCGGGTCATCGCGCTG0,53 478 SEQ ID 139 COMP ID 139 CCAGCGCGATGACCCG 174 189 SEQ IDCGGGTCATCGCGCTGG 0,23 479 SEQ ID 140 COMP ID 140 CCCAGCGCGATGACCC 175190 SEQ ID GGGTCATCGCGCTGGG 0,23 480 SEQ ID 141 COMP ID 141CCCCAGCGCGATGACC 176 191 SEQ ID GGTCATCGCGCTGGGG 0,42 481 SEQ ID 142COMP ID 142 ACCCCAGCGCGATGAC 177 192 SEQ ID GTCATCGCGCTGGGGT 0,30 482SEQ ID 143 COMP ID 143 GACCCCAGCGCGATGA 178 193 SEQ ID TCATCGCGCTGGGGTC0,63 483 SEQ ID 144 COMP ID 144 AGACCCCAGCGCGATG 179 194 SEQ IDCATCGCGCTGGGGTCT 0,57 484 SEQ ID 145 COMP ID 145 CAGACCCCAGCGCGAT 180195 SEQ ID ATCGCGCTGGGGTCTG 0,31 485 SEQ ID 146 COMP ID 146ACAGACCCCAGCGCGA 181 196 SEQ ID TCGCGCTGGGGTCTGT 0,29 486 SEQ ID 147COMP ID 147 TACAGACCCCAGCGCG 182 197 SEQ ID CGCGCTGGGGTCTGTA 0,34 487SEQ ID 148 COMP ID 148 CTACAGACCCCAGCGC 183 198 SEQ ID GCGCTGGGGTCTGTAG0,32 488 SEQ ID 149 COMP ID 149 ACTACAGACCCCAGCG 184 199 SEQ IDCGCTGGGGTCTGTAGT 0,34 489 SEQ ID 150 COMP ID 150 GACTACAGACCCCAGC 185200 SEQ ID GCTGGGGTCTGTAGTC 0,64 490 SEQ ID 151 COMP ID 151AGACTACAGACCCCAG 186 201 SEQ ID CTGGGGTCTGTAGTCT 0,95 491 SEQ ID 152COMP ID 152 CAGACTACAGACCCCA 187 202 SEQ ID TGGGGTCTGTAGTCTG 0,52 492SEQ ID 153 COMP ID 153 TCAGACTACAGACCCC 188 203 SEQ ID GGGGTCTGTAGTCTGA0,53 493 SEQ ID 154 COMP ID 154 CTCAGACTACAGACCC 189 204 SEQ IDGGGTCTGTAGTCTGAG 0,43 494 SEQ ID 155 COMP ID 155 GCTCAGACTACAGACC 190205 SEQ ID GGTCTGTAGTCTGAGC 0,33 495 SEQ ID 156 COMP ID 156CGCTCAGACTACAGAC 191 206 SEQ ID GTCTGTAGTCTGAGCG 0,43 496 SEQ ID 157COMP ID 157 GCGCTCAGACTACAGA 192 207 SEQ ID TCTGTAGTCTGAGCGC 0,46 497SEQ ID 158 COMP ID 158 AGCGCTCAGACTACAG 193 208 SEQ ID CTGTAGTCTGAGCGCT0,80 498 SEQ ID 159 COMP ID 159 TAGCGCTCAGACTACA 194 209 SEQ IDTGTAGTCTGAGCGCTA 0,47 499 SEQ ID 160 COMP ID 160 GTAGCGCTCAGACTAC 195210 SEQ ID GTAGTCTGAGCGCTAC 0,67 500 SEQ ID 161 COMP ID 161GGTAGCGCTCAGACTA 196 211 SEQ ID TAGTCTGAGCGCTACC 0,74 501 SEQ ID 162COMP ID 162 GGGTAGCGCTCAGACT 197 212 SEQ ID AGTCTGAGCGCTACCC 0,62 502SEQ ID 163 COMP ID 163 CGGGTAGCGCTCAGAC 198 213 SEQ ID GTCTGAGCGCTACCCG0,43 503 SEQ ID 164 COMP ID 164 CCGGGTAGCGCTCAGA 199 214 SEQ IDTCTGAGCGCTACCCGG 0,38 504 SEQ ID 165 COMP ID 165 ACCGGGTAGCGCTCAG 200215 SEQ ID CTGAGCGCTACCCGGT 0,45 505 SEQ ID 166 COMP ID 166AACCGGGTAGCGCTCA 201 216 SEQ ID TGAGCGCTACCCGGTT 0,61 506 SEQ ID 167COMP ID 167 CAACCGGGTAGCGCTC 202 217 SEQ ID GAGCGCTACCCGGTTG 0,56 507SEQ ID 168 COMP ID 168 GCAACCGGGTAGCGCT 203 218 SEQ ID AGCGCTACCCGGTTGC0,50 508 SEQ ID 169 COMP ID 169 AGCAACCGGGTAGCGC 204 219 SEQ IDGCGCTACCCGGTTGCT 0,35 509 SEQ ID 170 COMP ID 170 CAGCAACCGGGTAGCG 205220 SEQ ID CGCTACCCGGTTGCTG 0,21 510 SEQ ID 171 COMP ID 171GCAGCAACCGGGTAGC 206 221 SEQ ID GCTACCCGGTTGCTGC 0,19 511 SEQ ID 172COMP ID 172 AGCAGCAACCGGGTAG 207 222 SEQ ID CTACCCGGTTGCTGCT 0,26 512SEQ ID 173 COMP ID 173 CAGCAGCAACCGGGTA 208 223 SEQ ID TACCCGGTTGCTGCTG0,22 513 SEQ ID 174 COMP ID 174 GCAGCAGCAACCGGGT 209 224 SEQ IDACCCGGTTGCTGCTGC 0,42 514 SEQ ID 175 COMP ID 175 GGCAGCAGCAACCGGG 210225 SEQ ID CCCGGTTGCTGCTGCC 0,41 515 SEQ ID 176 COMP ID 176GGGCAGCAGCAACCGG 211 226 SEQ ID CCGGTTGCTGCTGCCC 0,44 516 SEQ ID 177COMP ID 177 TGGGCAGCAGCAACCG 212 227 SEQ ID CGGTTGCTGCTGCCCA 0,42 517SEQ ID 178 COMP ID 178 TTGGGCAGCAGCAACC 213 228 SEQ ID GGTTGCTGCTGCCCAA0,36 518 SEQ ID 179 COMP ID 179 CTTGGGCAGCAGCAAC 214 229 SEQ IDGTTGCTGCTGCCCAAG 0,28 519 SEQ ID 180 COMP ID 180 CCTTGGGCAGCAGCAA 215230 SEQ ID TTGCTGCTGCCCAAGG 0,31 520 SEQ ID 181 COMP ID 181TCCTTGGGCAGCAGCA 216 231 SEQ ID TGCTGCTGCCCAAGGA 0,26 521 SEQ ID 182COMP ID 182 GTCCTTGGGCAGCAGC 217 232 SEQ ID GCTGCTGCCCAAGGAC 0,60 522SEQ ID 183 COMP ID 183 GGTCCTTGGGCAGCAG 218 233 SEQ ID CTGCTGCCCAAGGACC0,39 523 SEQ ID 184 COMP ID 184 CGGTCCTTGGGCAGCA 219 234 SEQ IDTGCTGCCCAAGGACCG 0,30 524 SEQ ID 185 COMP ID 185 GCGGTCCTTGGGCAGC 220235 SEQ ID GCTGCCCAAGGACCGC 0,44 525 SEQ ID 186 COMP ID 186CGCGGTCCTTGGGCAG 221 236 SEQ ID CTGCCCAAGGACCGCG 0,21 526 SEQ ID 187COMP ID 187 CCGCGGTCCTTGGGCA 222 237 SEQ ID TGCCCAAGGACCGCGG 0,25 527SEQ ID 188 COMP ID 188 TCCGCGGTCCTTGGGC 223 238 SEQ ID GCCCAAGGACCGCGGA0,21 528 SEQ ID 189 COMP ID 189 CTCCGCGGTCCTTGGG 224 239 SEQ IDCCCAAGGACCGCGGAG 0,25 529 SEQ ID 190 COMP ID 190 ACTCCGCGGTCCTTGG 225240 SEQ ID CCAAGGACCGCGGAGT 0,55 530 SEQ ID 191 COMP ID 191GACTCCGCGGTCCTTG 226 241 SEQ ID CAAGGACCGCGGAGTC 0,33 531 SEQ ID 192COMP ID 192 CGACTCCGCGGTCCTT 227 242 SEQ ID AAGGACCGCGGAGTCG 0,49 532SEQ ID 193 COMP ID 193 CCGACTCCGCGGTCCT 228 243 SEQ ID AGGACCGCGGAGTCGG0,23 533 SEQ ID 194 COMP ID 194 TCCGACTCCGCGGTCC 229 244 SEQ IDGGACCGCGGAGTCGGA 0,20 534 SEQ ID 195 COMP ID 195 GTCCGACTCCGCGGTC 230245 SEQ ID GACCGCGGAGTCGGAC 0,25 535 SEQ ID 196 COMP ID 196CGTCCGACTCCGCGGT 231 246 SEQ ID ACCGCGGAGTCGGACG 0,55 536 SEQ ID 197COMP ID 197 GCGTCCGACTCCGCGG 232 247 SEQ ID CCGCGGAGTCGGACGC 0,41 537SEQ ID 198 COMP ID 198 TGCGTCCGACTCCGCG 233 248 SEQ ID CGCGGAGTCGGACGCA0,33 538 SEQ ID 199 COMP ID 199 CTGCGTCCGACTCCGC 234 249 SEQ IDGCGGAGTCGGACGCAG 0,180,47 539 SEQ ID 200 COMP ID 200 CCTGCGTCCGACTCCG235 250 SEQ ID CGGAGTCGGACGCAGG 0,140,60 540 SEQ ID 201 COMP ID 201GCCTGCGTCCGACTCC 236 251 SEQ ID GGAGTCGGACGCAGGC 0,150,62 541 SEQ ID 202COMP ID 202 TGCCTGCGTCCGACTC 237 252 SEQ ID GAGTCGGACGCAGGCA 0,230,65542 SEQ ID 203 COMP ID 203 CTGCCTGCGTCCGACT 238 253 SEQ IDAGTCGGACGCAGGCAG 0,270,85 543 SEQ ID 204 COMP ID 204 TCTGCCTGCGTCCGAC239 254 SEQ ID GTCGGACGCAGGCAGA 0,270,81 544 SEQ ID 205 COMP ID 205GTCTGCCTGCGTCCGA 240 255 SEQ ID TCGGACGCAGGCAGAC 0,220,53 545 SEQ ID 206COMP ID 206 GGTCTGCCTGCGTCCG 241 256 SEQ ID CGGACGCAGGCAGACC 0,330,80546

Example 5

Antisense oligonucleotides were designed for the 5′ UTR from position119 to 158 according to RefSeq NM_002087.3 (SEQ ID NO 1) with onenucleotide basepair shift as shown in table 2, which also provides thedata from the luciferase assay, were a value of greater than 1 indicatesan increased expression of progranulin (i.e. progranulin agonistactivity of the antisense oligonucleotide), and a value lower than 1indicates a decreased expression of progranulin (i.e. an inhibition orantagonistic effect, on progranulin expression).

The results from example 4 and 5 show that antisense oligonucleotideagonism was identified for several compounds targeting the progranulin5′UTR, particularly compounds with a contiguous nucleotide complementaryto nucleotides 1-229 of SEQ ID NO 1, such as compounds complementary toSEQ ID NO 445, SEQ ID NO: 446, SEQ ID NO: 459, SEQ ID NO 465, SEQ ID NO683, SEQ ID NO 568, SEQ ID NO 571, SEQ ID NO 575, SEQ ID NO 576, SEQ IDNO 577, SEQ ID NO 578, SEQ ID NO 584, & SEQ ID NO 586.

Compounds 105, 106, 119, 125, 117, 228, 231, 235-8, 244 and 246 wereidentified as having progranulin agonist activity in the luciferaseassay.

TABLE 2All the antisense oligonucleotides are designed as 18-mers DNA-LNA mixmers with a phosphorothioatebackbone, DNA-LNA mixmers with a phosphorothioate backbone, LNA at the very 5′ and 3′ position ande.g. LNA for every 2^(nd) or 3^(rd) nucleotide (see Compound table).Compound RefSeq Relative ID Number- NM_002087.3 Target luciferase SeeOligonucleotide (SEQ ID NO 1) Site activity Compound Sequence MotifStart End Sequence Target Relative  SEQ ID Table (nucleobase Sequence)Position Position ID Site Sequence to PBS) SEQ COMP IDGCTCCCATTGGCTACTTA 119 136 SEQ ID TAAGTAGCCAATGGGAGC 0,32 ID#207 207 547SEQ COMP ID CGCTCCCATTGGCTACTT 120 137 SEQ ID AAGTAGCCAATGGGAGCG 0,22ID#208 208 548 SEQ COMP ID CCGCTCCCATTGGCTACT 121 138 SEQ IDAGTAGCCAATGGGAGCGG 0,19 ID#209 209 549 SEQ COMP ID CCCGCTCCCATTGGCTAC122 139 SEQ ID GTAGCCAATGGGAGCGGG 0,24 ID#210 210 550 SEQ COMP IDACCCGCTCCCATTGGCTA 123 140 SEQ ID TAGCCAATGGGAGCGGGT 0,37 ID#211 211 551SEQ COMP ID TACCCGCTCCCATTGGCT 124 141 SEQ ID AGCCAATGGGAGCGGGTA 0,38ID#212 212 552 SEQ COMP ID CTACCCGCTCCCATTGGC 125 142 SEQ IDGCCAATGGGAGCGGGTAG 0,39 ID#213 213 553 SEQ COMP ID GCTACCCGCTCCCATTGG126 143 SEQ ID CCAATGGGAGCGGGTAGC 0,47 ID#214 214 554 SEQ COMP IDGGCTACCCGCTCCCATTG 127 144 SEQ ID CAATGGGAGCGGGTAGCC 0,55 ID#215 215 555SEQ COMP ID GGGCTACCCGCTCCCATT 128 145 SEQ ID AATGGGAGCGGGTAGCCC 0,53ID#216 216 556 SEQ COMP ID AGGGCTACCCGCTCCCAT 129 146 SEQ IDATGGGAGCGGGTAGCCCT 0,56 ID#217 217 557 SEQ COMP ID CAGGGCTACCCGCTCCCA130 147 SEQ ID TGGGAGCGGGTAGCCCTG 0,49 ID#218 218 558 SEQ COMP IDTCAGGGCTACCCGCTCCC 131 148 SEQ ID GGGAGCGGGTAGCCCTGA 0,58 ID#219 219 559SEQ COMP ID ATCAGGGCTACCCGCTCC 132 149 SEQ ID GGAGCGGGTAGCCCTGAT 0,48ID#220 220 560 SEQ COMP ID GATCAGGGCTACCCGCTC 133 150 SEQ IDGAGCGGGTAGCCCTGATC 0,49 ID#221 221 561 SEQ COMP ID GGATCAGGGCTACCCGCT134 151 SEQ ID AGCGGGTAGCCCTGATCC 0,38 ID#222 222 562 SEQ COMP IDGGGATCAGGGCTACCCGC 135 152 SEQ ID GCGGGTAGCCCTGATCCC 0,33 ID#223 223 563SEQ COMP ID AGGGATCAGGGCTACCCG 136 153 SEQ ID CGGGTAGCCCTGATCCCT 0,36ID#224 224 564 SEQ COMP ID CAGGGATCAGGGCTACCC 137 154 SEQ IDGGGTAGCCCTGATCCCTG 0,48 ID#225 225 565 SEQ COMP ID CCAGGGATCAGGGCTACC138 155 SEQ ID GGTAGCCCTGATCCCTGG 0,69 ID#226 226 566 SEQ COMP IDGCCAGGGATCAGGGCTAC 139 156 SEQ ID GTAGCCCTGATCCCTGGC 0,94 ID#227 227 567SEQ COMP ID GGCCAGGGATCAGGGCTA 140 157 SEQ ID TAGCCCTGATCCCTGGCC 1,15ID#228 228 568 SEQ COMP ID TGGCCAGGGATCAGGGCT 141 158 SEQ IDAGCCCTGATCCCTGGCCA 0,92 ID#229 229 569 SEQ COMP ID TTGGCCAGGGATCAGGGC142 159 SEQ ID GCCCTGATCCCTGGCCAA 0,85 ID#230 230 570 SEQ COMP IDATTGGCCAGGGATCAGGG 143 160 SEQ ID CCCTGATCCCTGGCCAAT 1,12 ID#231 231 571SEQ COMP ID CATTGGCCAGGGATCAGG 144 161 SEQ ID CCTGATCCCTGGCCAATG 0,72ID#232 232 572 SEQ COMP ID CCATTGGCCAGGGATCAG 145 162 SEQ IDCTGATCCCTGGCCAATGG 0,75 ID#233 233 573 SEQ COMP ID TCCATTGGCCAGGGATCA146 163 SEQ ID TGATCCCTGGCCAATGGA 0,97 ID#234 234 574 SEQ COMP IDTTCCATTGGCCAGGGATC 147 164 SEQ ID GATCCCTGGCCAATGGAA 1,22 ID#235 235 575SEQ COMP ID TTTCCATTGGCCAGGGAT 148 165 SEQ ID ATCCCTGGCCAATGGAAA 1,13ID#236 236 576 SEQ COMP ID GTTTCCATTGGCCAGGGA 149 166 SEQ IDTCCCTGGCCAATGGAAAC 1,01 ID#237 237 577 SEQ COMP ID AGTTTCCATTGGCCAGGG150 167 SEQ ID CCCTGGCCAATGGAAACT 1,09 ID#238 238 578 SEQ COMP IDCAGTTTCCATTGGCCAGG 151 168 SEQ ID CCTGGCCAATGGAAACTG 0,79 ID#239 239 579SEQ COMP ID TCAGTTTCCATTGGCCAG 152 169 SEQ ID CTGGCCAATGGAAACTGA 0,69ID#240 240 580 SEQ COMP ID CTCAGTTTCCATTGGCCA 153 170 SEQ IDTGGCCAATGGAAACTGAG 0,59 ID#241 241 581 SEQ COMP ID CCTCAGTTTCCATTGGCC154 171 SEQ ID GGCCAATGGAAACTGAGG 0,39 ID#242 242 582 SEQ COMP IDACCTCAGTTTCCATTGGC 155 172 SEQ ID GCCAATGGAAACTGAGGT 0,95 ID#243 243 583SEQ COMP ID TACCTCAGTTTCCATTGG 156 173 SEQ ID CCAATGGAAACTGAGGTA 1,12ID#244 244 584 SEQ COMP ID CTACCTCAGTTTCCATTG 157 174 SEQ IDCAATGGAAACTGAGGTAG 1,00 ID#245 245 585 SEQ COMP ID CCTACCTCAGTTTCCATT158 175 SEQ ID AATGGAAACTGAGGTAGG 1,26 ID#246 246 586

Example 6

Antisense oligonucleotides were designed for the 3′ UTR from position2044 to 2346 according to RefSeq NM_002807.3 with three nucleotidebasepar shift as shown in table 3 which also provides the data from theluciferase assay, were a value of greater than 1 indicates an increasedexpression of progranulin (i.e. progranulin agonist activity of theantisense oligonucleotide), and a value lower than 1 indicates adecreased expression of progranulin (i.e. an inhibition or antagonisticeffect, on progranulin expression).

The data shows antisense oligonucleotide antisense oligonucleotides withprogranulin agonist activity that are complementary to the 3′UTR regionof a human progranulin mRNA transcript were identified, for examplecompounds with a contiguous nucleotide sequence which is complementaryto a sequence selected from the group consisting of SEQ ID NO 684, 685,683, 686, 687, and 688, such as compounds with a contiguous nucleotidesequence which is complementary to a sequence selected from the groupconsisting of 607, 608, 609, 610, 611, 612, 619, 620, 633, 640, 641,645,651, and 652.

Compounds 263, 267, 269-272, 279, 280, 293, 300, 301, 305, 311, 312 and327 were identified as exhibiting progranulin agonist activity in theluciferase assay system used.

TABLE 3All the antisense oligonucleotides are designed as 18-mers DNA-LNA mixmers with a phosphorothioatebackbone, DNA-LNA mixmers with a phosphorothioate backbone, LNA at the very 5′ and 3′ position ande.g. LNA for every 2^(nd) or 3^(rd) nucleotide (see Compound table).RefSeq Relative NM_002087.3 Target luciferase Compound Oligonucleotide(SEQ ID NO 1) Site activity SEQ ID # (see Sequence Motif Start EndSequence Target Relative ID Compound (nucleobase Sequence) PositionPosition ID Site Sequence to PBS) SEQ COMP ID 5′-TGCAGAGTCTTCAGTACT-3′2044 2061 SEQ ID AGTACTGAAGACTCTGCA 0,46 ID 247 587 #247 SEQ COMP ID5′-GGCTGCAGAGTCTTCAGT-3′ 2047 2064 SEQ ID ACTGAAGACTCTGCAGCC 0,25 ID 248588 #248 SEQ COMP ID 5′-GAGGGCTGCAGAGTCTTC-3′ 2050 2067 SEQ IDGAAGACTCTGCAGCCCTC 0,35 ID 249 589 #249 SEQ COMP ID5′-CCCGAGGGCTGCAGAGTC-3′ 2053 2070 SEQ ID GACTCTGCAGCCCTCGGG 0,65 ID 250590 #250 SEQ COMP ID 5′-GGTCCCGAGGGCTGCAGA-3′ 2056 2073 SEQ IDTCTGCAGCCCTCGGGACC 0,69 ID 251 591 #251 SEQ COMP ID5′-TGGGGTCCCGAGGGCTGC-3′ 2059 2076 SEQ ID GCAGCCCTCGGGACCCCA 0,37 ID 252592 #252 SEQ COMP ID 5′-GAGTGGGGTCCCGAGGGC-3′ 2062 2079 SEQ IDGCCCTCGGGACCCCACTC 0,77 ID 253 593 #253 SEQ COMP ID5′-TCCGAGTGGGGTCCCGAG-3′ 2065 2082 SEQ ID CTCGGGACCCCACTCGGA 0,75 ID 254594 #254 SEQ COMP ID 5′-CCCTCCGAGTGGGGTCCC-3′ 2068 2085 SEQ IDGGGACCCCACTCGGAGGG 0,67 ID 255 595 #255 SEQ COMP ID5′-GCACCCTCCGAGTGGGGT-3′ 2071 2088 SEQ ID ACCCCACTCGGAGGGTGC 0,57 ID 256596 #256 SEQ COMP ID 5′-AGGGCACCCTCCGAGTGG-3′ 2074 2091 SEQ IDCCACTCGGAGGGTGCCCT 0,78 ID 257 597 #257 SEQ COMP ID5′-CAGAGGGCACCCTCCGAG-3′ 2077 2094 SEQ ID CTCGGAGGGTGCCCTCTG 0,92 ID 258598 #258 SEQ COMP ID 5′-GAGCAGAGGGCACCCTCC-3′ 2080 2097 SEQ IDGGAGGGTGCCCTCTGCTC 0,29 ID 259 599 #259 SEQ COMP ID5′-CCTGAGCAGAGGGCACCC-3′ 2083 2100 SEQ ID GGGTGCCCTCTGCTCAGG 0,63 ID 260600 #260 SEQ COMP ID 5′-AGGCCTGAGCAGAGGGCA-3′ 2086 2103 SEQ IDTGCCCTCTGCTCAGGCCT 0,56 ID 261 601 #261 SEQ COMP ID5′-GGGAGGCCTGAGCAGAGG-3′ 2089 2106 SEQ ID CCTCTGCTCAGGCCTCCC 0,74 ID 262602 #262 SEQ COMP ID 5′-CTAGGGAGGCCTGAGCAG-3′ 2092 2109 SEQ IDCTGCTCAGGCCTCCCTAG 1,13 ID 263 603 #263 SEQ COMP ID5′-GTGCTAGGGAGGCCTGAG-3′ 2095 2112 SEQ ID CTCAGGCCTCCCTAGCAC 0,99 ID 264604 #264 SEQ COMP ID 5′-GAGGTGCTAGGGAGGCCT-3′ 2098 2115 SEQ IDAGGCCTCCCTAGCACCTC 0,83 ID 265 605 #265 SEQ COMP ID5′-GGGGAGGTGCTAGGGAGG-3′ 2101 2118 SEQ ID CCTCCCTAGCACCTCCCC 0,89 ID 266606 #266 SEQ COMP ID 5′-TAGGGGGAGGTGCTAGGG-3′ 2104 2121 SEQ IDCCCTAGCACCTCCCCCTA 1,27 ID 267 607 #267 SEQ COMP ID5′-GGTTAGGGGGAGGTGCTA-3′ 2107 2124 SEQ ID TAGCACCTCCCCCTAACC 0,58 ID 268608 #268 SEQ COMP ID 5′-TTTGGTTAGGGGGAGGTG-3′ 2110 2127 SEQ IDCACCTCCCCCTAACCAAA 1,09 ID 269 609 #269 SEQ COMP ID5′-GAATTTGGTTAGGGGGAG-3′ 2113 2130 SEQ ID CTCCCCCTAACCAAATTC 1,24 ID 270610 #270 SEQ COMP ID 5′-GGAGAATTTGGTTAGGGG-3′ 2116 2133 SEQ IDCCCCTAACCAAATTCTCC 1,05 ID 271 611 #271 SEQ COMP ID5′-CAGGGAGAATTTGGTTAG-3′ 2119 2136 SEQ ID CTAACCAAATTCTCCCTG 1,04 ID 272612 #272 SEQ COMP ID 5′-GTCCAGGGAGAATTTGGT-3′ 2122 2139 SEQ IDACCAAATTCTCCCTGGAC 0,94 ID 273 613 #273 SEQ COMP ID5′-GGGGTCCAGGGAGAATTT-3′ 2125 2142 SEQ ID AAATTCTCCCTGGACCCC 0,89 ID 274614 #274 SEQ COMP ID 5′-AATGGGGTCCAGGGAGAA-3′ 2128 2145 SEQ IDTTCTCCCTGGACCCCATT 0,99 ID 275 615 #275 SEQ COMP ID5′-CAGAATGGGGTCCAGGGA-3′ 2131 2148 SEQ ID TCCCTGGACCCCATTCTG 0,60 ID 276616 #276 SEQ COMP ID 5′-GCTCAGAATGGGGTCCAG-3′ 2134 2151 SEQ IDCTGGACCCCATTCTGAGC 0,52 ID 277 617 #277 SEQ COMP ID5′-GGAGCTCAGAATGGGGTC-3′ 2137 2154 SEQ ID GACCCCATTCTGAGCTCC 0,91 ID 278618 #278 SEQ COMP ID 5′-TGGGGAGCTCAGAATGGG-3′ 2140 2157 SEQ IDCCCATTCTGAGCTCCCCA 1,14 ID 279 619 #279 SEQ COMP ID5′-TGATGGGGAGCTCAGAAT-3′ 2143 2160 SEQ ID ATTCTGAGCTCCCCATCA 1,11 ID 280620 #280 SEQ COMP ID 5′-TGGTGATGGGGAGCTCAG-3′ 2146 2163 SEQ IDCTGAGCTCCCCATCACCA 0,97 ID 281 621 #281 SEQ COMP ID5′-CCATGGTGATGGGGAGCT-3′ 2149 2166 SEQ ID AGCTCCCCATCACCATGG 0,97 ID 282622 #282 SEQ COMP ID 5′-CTCCCATGGTGATGGGGA-3′ 2152 2169 SEQ IDTCCCCATCACCATGGGAG 0,81 ID 283 623 #283 SEQ COMP ID5′-CACCTCCCATGGTGATGG-3′ 2155 2172 SEQ ID CCATCACCATGGGAGGTG 0,69 ID 284624 #284 SEQ COMP ID 5′-CCCCACCTCCCATGGTGA-3′ 2158 2175 SEQ IDTCACCATGGGAGGTGGGG 0,69 ID 285 625 #285 SEQ COMP ID5′-AGGCCCCACCTCCCATGG-3′ 2161 2178 SEQ ID CCATGGGAGGTGGGGCCT 0,58 ID 286626 #286 SEQ COMP ID 5′-TTGAGGCCCCACCTCCCA-3′ 2164 2181 SEQ IDTGGGAGGTGGGGCCTCAA 0,47 ID 287 627 #287 SEQ COMP ID5′-AGATTGAGGCCCCACCTC-3′ 2167 2184 SEQ ID GAGGTGGGGCCTCAATCT 0,59 ID 288628 #288 SEQ COMP ID 5′-CTTAGATTGAGGCCCCAC-3′ 2170 2187 SEQ IDGTGGGGCCTCAATCTAAG 0,38 ID 289 629 #289 SEQ COMP ID5′-GGCCTTAGATTGAGGCCC-3′ 2173 2190 SEQ ID GGGCCTCAATCTAAGGCC 0,43 ID 290630 #290 SEQ COMP ID 5′-GAAGGCCTTAGATTGAGG-3′ 2176 2193 SEQ IDCCTCAATCTAAGGCCTTC 0,76 ID 291 631 #291 SEQ COMP ID5′-AGGGAAGGCCTTAGATTG-3′ 2179 2196 SEQ ID CAATCTAAGGCCTTCCCT 0,86 ID 292632 #292 SEQ COMP ID 5′-GACAGGGAAGGCCTTAGA-3′ 2182 2199 SEQ IDTCTAAGGCCTTCCCTGTC 1,04 ID 293 633 #293 SEQ COMP ID5′-TCTGACAGGGAAGGCCTT-3′ 2185 2202 SEQ ID AAGGCCTTCCCTGTCAGA 0,81 ID 294634 #294 SEQ COMP ID 5′-CCTTCTGACAGGGAAGGC-3′ 2188 2205 SEQ IDGCCTTCCCTGTCAGAAGG 0,89 ID 295 635 #295 SEQ COMP ID5′-CCCCCTTCTGACAGGGAA-3′ 2191 2208 SEQ ID TTCCCTGTCAGAAGGGGG 0,71 ID 296636 #296 SEQ COMP ID 5′-CAACCCCCTTCTGACAGG-3′ 2194 2211 SEQ IDCCTGTCAGAAGGGGGTTG 0,89 ID 297 637 #297 SEQ COMP ID5′-CCACAACCCCCTTCTGAC-3′ 2197 2214 SEQ ID GTCAGAAGGGGGTTGTGG 0,42 ID 298638 #298 SEQ COMP ID 5′-TTGCCACAACCCCCTTCT-3′ 2200 2217 SEQ IDAGAAGGGGGTTGTGGCAA 0,88 ID 299 639 #299 SEQ COMP ID5′-CTTTTGCCACAACCCCCT-3′ 2203 2220 SEQ ID AGGGGGTTGTGGCAAAAG 1,16 ID 300640 #300 SEQ COMP ID 5′-TGGCTTTTGCCACAACCC-3′ 2206 2223 SEQ IDGGGTTGTGGCAAAAGCCA 1,08 ID 301 641 #301 SEQ COMP ID5′-ATGTGGCTTTTGCCACAA-3′ 2209 2226 SEQ ID TTGTGGCAAAAGCCACAT 1,01 ID 302642 #302 SEQ COMP ID 5′-GTAATGTGGCTTTTGCCA-3′ 2212 2229 SEQ IDTGGCAAAAGCCACATTAC 0,55 ID 303 643 #303 SEQ COMP ID5′-CTTGTAATGTGGCTTTTG-3′ 2215 2232 SEQ ID CAAAAGCCACATTACAAG 1,01 ID 304644 #304 SEQ COMP ID 5′-CAGCTTGTAATGTGGCTT-3′ 2218 2235 SEQ IDAAGCCACATTACAAGCTG 1,50 ID 305 645 #305 SEQ COMP ID5′-TGGCAGCTTGTAATGTGG-3′ 2221 2238 SEQ ID CCACATTACAAGCTGCCA 0,96 ID 306646 #306 SEQ COMP ID 5′-GGATGGCAGCTTGTAATG-3′ 2224 2241 SEQ IDCATTACAAGCTGCCATCC 0,74 ID 307 647 #307 SEQ COMP ID5′-AGGGGATGGCAGCTTGTA-3′ 2227 2244 SEQ ID TACAAGCTGCCATCCCCT 0,84 ID 308648 #308 SEQ COMP ID 5′-GGGAGGGGATGGCAGOTT-3′ 2230 2247 SEQ IDAAGCTGCCATCCCCTCCC 0,63 ID 309 649 #309 SEQ COMP ID5′-ACGGGGAGGGGATGGCAG-3 2233 2250 SEQ ID CTGCCATCCCCTCCCCGT 0,71 ID 310650 #310 SEQ COMP ID 5′-GAAACGGGGAGGGGATGG-3′ 2236 2253 SEQ IDCCATCCCCTCCCCGTTTC 1,06 ID 311 651 #311 SEQ COMP ID5′-ACTGAAACGGGGAGGGGA-3′ 2239 2256 SEQ ID TCCCCTCCCCGTTTCAGT 1,08 ID 312652 #312 SEQ COMP ID 5′-TCCACTGAAACGGGGAGG-3′ 2242 2259 SEQ IDCCTCCCCGTTTCAGTGGA 0,53 ID 313 653 #313 SEQ COMP ID5′-GGGTCCACTGAAACGGGG-3′ 2245 2262 SEQ ID CCCCGTTTCAGTGGACCC 0,93 ID 314654 #314 SEQ COMP ID 5′-ACAGGGTCCACTGAAACG-3′ 2248 2265 SEQ IDCGTTTCAGTGGACCCTGT 0,49 ID 315 655 #315 SEQ COMP ID5′-GCCACAGGGTCCACTGAA-3′ 2251 2268 SEQ ID TTCAGTGGACCCTGTGGC 0,57 ID 316656 #316 SEQ COMP ID 5′-CTGGCCACAGGGTCCACT-3′ 2254 2271 SEQ IDAGTGGACCCTGTGGCCAG 0,51 ID 317 657 #317 SEQ COMP ID5′-CACCTGGCCACAGGGTCC-3′ 2257 2274 SEQ ID GGACCCTGTGGCCAGGTG 0,73 ID 318658 #318 SEQ COMP ID 5′-AAGCACCTGGCCACAGGG-3′ 2260 2277 SEQ IDCCCTGTGGCCAGGTGCTT 0,43 ID 319 659 #319 SEQ COMP ID5′-GAAAAGCACCTGGCCACA-3′ 2263 2280 SEQ ID TGTGGCCAGGTGCTTTTC 0,33 ID 320660 #320 SEQ COMP ID 5′-AGGGAAAAGCACCTGGCC-3′ 2266 2283 SEQ IDGGCCAGGTGCTTTTCCCT 0,16 ID 321 661 #321 SEQ COMP ID5′-GATAGGGAAAAGCACCTG-3′ 2269 2286 SEQ ID CAGGTGCTTTTCCCTATC 0,65 ID 322662 #322 SEQ COMP ID 5′-GTGGATAGGGAAAAGCAC-3′ 2272 2289 SEQ IDGTGCTTTTCCCTATCCAC 0,54 ID 323 663 #323 SEQ COMP ID5′-CCTGTGGATAGGGAAAAG-3′ 2275 2292 SEQ ID CTTTTCCCTATCCACAGG 0,63 ID 324664 #324 SEQ COMP ID 5′-ACCCCTGTGGATAGGGAA-3′ 2278 2295 SEQ IDTTCCCTATCCACAGGGGT 0,29 ID 325 665 #325 SEQ COMP ID5′-AACACCCCTGTGGATAGG-3′ 2281 2298 SEQ ID CCTATCCACAGGGGTGTT 0,62 ID 326666 #326 SEQ COMP ID 5′-ACAAACACCCCTGTGGAT-3′ 2284 2301 SEQ IDATCCACAGGGGTGTTTGT 1,08 ID 327 667 #327 SEQ COMP ID5′-CACACAAACACCCCTGTG-3′ 2287 2304 SEQ ID CACAGGGGTGTTTGTGTG 0,81 ID 328668 #328 SEQ COMP ID 5′-ACACACACAAACACCCCT-3′ 2290 2307 SEQ IDAGGGGTGTTTGTGTGTGT 0,88 ID 329 669 #329 SEQ COMP ID5′-CGCACACACACAAACACC-3′ 2293 2310 SEQ ID GGTGTTTGTGTGTGTGCG 0,60 ID 330670 #330 SEQ COMP ID 5′-ACGCGCACACACACAAAC-3′ 2296 2313 SEQ IDGTTTGTGTGTGTGCGCGT 0,68 ID 331 671 #331 SEQ COMP ID5′-CACACGCGCACACACACA-3′ 2299 2316 SEQ ID TGTGTGTGTGCGCGTGTG 0,51 ID 332672 #332 SEQ COMP ID 5′-ACGCACACGCGCACACAC-3′ 2302 2319 SEQ IDGTGTGTGCGCGTGTGCGT 0,25 ID 333 673 #333 SEQ COMP ID5′-GAAACGCACACGCGCACA-3′ 2305 2322 SEQ ID TGTGCGCGTGTGCGTTTC 0,66 ID 334674 #334 SEQ COMP ID 5′-ATTGAAACGCACACGCGC-3′ 2308 2325 SEQ IDGCGCGTGTGCGTTTCAAT 0,82 ID 335 675 #335 SEQ COMP ID5′-TTTATTGAAACGCACACG-3′ 2311 2328 SEQ ID CGTGTGCGTTTCAATAAA 0,76 ID 336676 #336 SEQ COMP ID 5′-AACTTTATTGAAACGCAC-3′ 2314 2331 SEQ IDGTGCGTTTCAATAAAGTT 0,73 ID 337 677 #337 SEQ COMP ID5′-ACAAACTTTATTGAAACG-3′ 2317 2334 SEQ ID CGTTTCAATAAAGTTTGT 0,84 ID 338678 #338 SEQ COMP ID 5′-TGTACAAACTTTATTGAA-3′ 2320 2337 SEQ IDTTCAATAAAGTTTGTACA 0,98 ID 339 679 #339 SEQ COMP ID5′-AAGTGTACAAACTTTATT-3′ 2323 2340 SEQ ID AATAAAGTTTGTACACTT 0,87 ID 340680 #340 SEQ COMP ID 5′-AGAAAGTGTACAAACTTT-3′ 2326 2343 SEQ IDAAAGTTTGTACACTTTCT 0,72 ID 341 681 #341 SEQ COMP ID5′-TTAAGAAAGTGTACAAAC-3′ 2329 2346 SEQ ID GTTTGTACACTTTCTTAA 0,87 ID 342682 #342

Example 7: 16-Mer Oligos Targeting the 5′ UTR

16-mer Oligos targeting 5′ UTR uORF region (SEQ ID Nos 95-136) wereselected, prepared and profiled for effects on Progranulin proteinexpression.

H4 neuroglioma cells were seeded in 96 well plates 5000 pr well, andtreated with 10 μM final concentration of compounds for 5 days in 200 μLmedium.

Microglia cells were chosen for analysis because these cells producehigh levels of progranulin. Reduction of progranulin in microglia cellsalone is sufficient to effect inflammation, lysosomal dysfunction, andhyperproliferation in a cell-autonomous manner. Therefore, targetingmicroglial dysfunction caused by progranulin insufficiency represents apotential therapeutic strategy to manage neurodegeneration inFrontotemporal dementia. To study effects on Progranulin in cellularsystems, H4 cells (ATCC HTB-148) a commercial available glial cell linederived from a cancer patient have been used for identifyingoligonucleotides capable of increasing progranulin production.

To further use Microglia that exhibit functional characteristics similarto human microglia, including phagocytosis and cytokine-mediatedinflammatory responses, and express relevant microglial markers, hiPSCderived microglia iCell® Microglia from FujiFilm Cellular Dynamics Inc.(Cat. no R1131) have been used for investigating effects of selectedoligonucleotides on progranulin production.

Progranulin expression levels were evaluated in media after dilution 1:8by ELISA from Abcam (ab252364). Compound #105, #106, #110, #113 and #114induced progranulin secretion more than 150% compared to PBS as shown inFIG. 1 .

Compounds #105, #106, #110 and #114 localise on the 5′ UTR of Proganulintranscript, targeting the uORF region as shown in FIG. 2 .

H4 cells were seeded in 96 well plates 5000 pr well, and treated with 10μM final concentration of compounds for 5 days in 200 μL medium.Progranulin expression levels were evaluated in cell lysate (RIPA lysisand extraction buffer from Pierce cat. No. 89900) using the WES platform(ProteinSimple) and GRN antibody Invitrogen PA5-27275 diluted 1:25 andHPRT1 antibody ab109021 (Abcam) diluted 1:50. GRN expression wasnormalized to endogenous housekeeping protein HPRT1.

Compounds #106, #110, and #114 induced Progranulin in cell lysatecompared to PBS as shown in FIGS. 3 and 4 .

Example 8: Compound #106

hiPSC derived microglia (iCell Microglia Kit, 01279, Cat. no R1131) wereseeded in 48 well plates with 100000 pr well in 500 μL, and were treatedwith varying concentrations of Compound #106 for 5 days.

Progranulin expression levels were evaluated in media after dilution 1:8by ELISA from Abcam (ab252364).

Compound #106 (n=3) dose-dependently induced Progranulin secretioncompared to PBS as shown in FIG. 5 .

Example 9: 18-Mer Oligos Targeting 5′ UTR

18-mer Oligos targeting 5′ UTR uORF region (SEQ ID NOs: 207-245) wereselected, prepared and profiled for effects on Progranulin proteinexpression.

H4 neuroglioma cells were seeded in 96 well plates 5000 pr well andtreated with 10 μM final concentration of compounds for 5 days in 200 μLmedium. Progranulin expression levels were evaluated in media afterdilution 1:8 by ELISA from Abcam (ab252364).

Compound #231 and #241 induced Progranulin secretion compared to PBS asshown in FIG. 6 .

Example 10: Compound #106

The structure of Compound ID #106 (SEQ ID NO 106) inducing upregulationof Progranulin in both H4 cells and hiPSC derived Microglia cells, isshown in FIG. 7 .

Example 11: Full 2′MOE and 2′oMe Modified Versions of SEQ ID NO: 106

SEQ ID NO: 106 (TGGCCAGGGATCAGGG) was tested as both a full 2′MOEmodified oligo (Compound #106 full 2′MOE) and a full 2′oMe modifiedoligo (Compound #106 full 2′oMe).

H4 neuroglioma cells seeded in 96 well plates 5000 pr well were treatedwith 10 μM final concentration of compounds for 5 days in 200 μL medium.Progranulin expression levels were evaluated in media after dilution 1:8by ELISA from Abcam (ab252364). Compound #106 and Compound #106 full2′MOE and Compound #106 full 2′oMe induced a ˜2-fold increase inprogranulin secretion to the media compared to PBS.

Example 12: Gene Transcript Regulation by Compound #106, Compound #106Full 2′MOE and Compound #106 Full 2′oMe

To understand the number of gene transcripts regulated by compound #106,Compound #106 full 2′MOE and Compound #106 full 2′oMe, H4 neurogliomacells seeded in 48 well plates 15000 per well were treated with 10 μMfinal concentration of compounds for 5 days in 500 μL medium. mRNA wasisolated using the MagNAPure 96 system (Roche) according tomanufacturer's protocol. The purified mRNA were sent for gene expressionarray analysis at Eurofins Genomics, using Clariom™ S Arrays(ThermoFisher Scientific). Expression analysis was conducted using theQlucore Omics Explorer software, using a two-group comparison and byadjusting the FDR<0.1. The number of genes regulated more than 2-foldeither up and down compared to PBS were identified. Compound #106 showed1207 genes regulated more than 2-fold, Compound #106 full 2′oMe showed782 genes regulated more than 2-fold, whereas Compound #106 full 2′MOEonly showed 43 transcripts regulated. FIG. 9 shows that Compound #106full 2′MOE has less off-targets compared to compound #106 and Compound#106 full 2′oMe.

The genes regulated more than 2-fold with a FDR<0.1 are shown below.

Genes regulated more than 2-fold with a FDR<0.1 following treatment withCompound #106: AATF, ABCA1, ABCC2, ABCC3, ABCG1, ABLIM3, ACAT2, ACKR3,ACSL5, ACSS3, ACTA2, ACVR1B, ADAM9, ADAMTS16, ADAMTS19, ADAMTS3,ADAMTSL4, ADGRA3, ADGRB3, ADI1, ADRBK1, ADRM1, ADSL, AFAP1, AGT, AHCY,AHI1, AHNAK2, AHR, AJAP1, AKAP6, ALCAM, ALDH1L2, ALDH3A1, ALDOA, ALDOC,ALG8, ALKBHS, ALPK2, ALYREF, AMMECR1, AMMECR1L, AMPD2, AMTN, ANGPT1,ANK3, ANKRD18A, ANKRD44, ANLN, ANO7, ANPEP, ANTXR2, ANXA1, AOAH, APCDD1,APEX1, APH1A, APOBEC3B, APOL2, APOL3, APRT, AQP1, AQP3, ARAF, ARCN1,ARHGAP11B, ARHGAP35, ARHGAP8, ARHGEF2, ARL4A, ARMC6, ARPC4, ARPC4-TTLL3,ARRDC3, ARRDC4, ARSG, ASNA1, ASNS, ASPM, ASS1, ATAD2, ATN1, ATP6AP1L,ATP6V0A1, ATP8B3, ATXN2, ATXN2L, AVEN, B4GALT5, BCAM, BCL6, BDNF, BEX1,BHLHE40, BIRC5, BLID, BLM, BMP5, BNC2, BNIP3, BNIP3L, BSG, BTAF1, BUB1B,C10orf10, C10orf107, C12orf76, C17orf89, C1RL, C1orf174, C1orf21,C1orf52, C1orf53, C20orf24, C7orf26, C7orf73, C8orf4, C8orf48, C8orf58,CA12, CA5B, CA9, CACNG4, CACYBP, CALCOCO1, CALR, CAMK4, CAPNS1, CAPZB,CASC5, CASK, CBLB, CCBL1, CCDC102B, CCDC150, CCDC163P, CCDC34, CCNA2,CCNB1, CCNB2, CCND1, CCNE2, CCPG1, CCT2, CD151, CD24, CD55, CD96, CD99,CD99, CDC20, CDC42SE1, CDC45, CDC6, CDCA5, CDCA8, CDH6, CDH8, CDK1,CDKN1A, CDKN3, CDT1, CENPA, CENPF, CENPH, CENPI, CENPM, CENPN, CENPU,CENPW, CEP128, CEP19, CEP55, CEP78, CFC1, CFH, CFI, CFL1, CHAC1, CHAC2,CHAF1B, CHMP1B, CHP1, CHST15, CKAP2, CKS2, CLEC2D, CLIC4, CLIP4, CLK2,CLMN, CLSPN, CLSTN2, CLTA, CLTB, CMTM7, CNTNAP1, CNTNAP3, CNTNAP3B,CNTNAP3B, CNTNAP3P2, COASY, COBLL1, COG7, COL1A1, COL21A1, COL3A1,COL5A2, COLEC12, COMMD3-BMI1, COPRS, COPZ1, CORIN, CORO2B, COX2, COX5A,CP, CPA4, CPD, CPSF3, CRISPLD1, CSF1, CSGALNACT1, CTBP2, CTBS, CTH,CTNND1, CTSB, CTSC, CTSL, CTSO, CUL7, CXADR, CXCL14, CXCL8, CYB5D2,CYTL1, DACT1, DBI, DBN1, DCTPP1, DDIT4, DDR2, DDX39A, DDX46, DECR1,DEDD, DEPDC1, DEPTOR, DGKD, DGKD, DGKD, DGKD, DGKD, DGKD, DHCR24, DHFR,DHRS3, DHX15, DHX9, DLGAP5, DLX1, DMKN, DOCK10, DPT, DPYD, DPYSL2,DPYSL3, DPYSL5, DSEL, DSN1, DSTN, DTNBP1, DUSP6, E2F8, EBI3, EBP, EDC4,EDEM1, EDIL3, EEF1B2, EEPD1, EFEMP2, EFTUD1, EGLN3, EGR1, EID1, EIF5,EIF5A, EIF6, ELAVL2, EMP1, ENC1, ENCASE, ENO2, ENPP1, ENPP2, ENTPD4,EPAS1, EPHX1, EPT1, ERGIC1, ERH, ERN1, ERO1A, ERRFI1, ETV1, ETV5, EXO1,EXT1, EXT1, EYA4, FAM101B, FAM111A, FAM111B, FAM114A1, FAM127B, FAM13A,FAM13C, FAM155A, FAM155A, FAM155A, FAM160A2, FAM161A, FAM162A, FAM200B,FAM20B, FAM214B, FAM219A, FAM234A, FAM46A, FAM83D, FANCA, FANCD2, FANC1,FBL, FBN1, FBXO32, FBXO36, FBXO44, FBXO7, FCHSD1, FDPS, FDX1L, FEM1C,FEM1C, FEN1, FGF7, FH, FIBIN, FJX1, FKBP10, FKBP1A, FKBP1A-SDCBP2,FKBP9, FLOT1, FLOT2, FLRT2, FN1, FNBP4, FOSL1, FOSL2, FOXF1, FOXF2,FOXK1, FOXM1, FRMD4B, FSCN1, FSTL1, FSTL4, FTSJ2, FUCA1, FUNDC2, FURIN,FUS, FUT11, FXYD5, FYCO1, GABRE, GALNT1, GALNT13, GANAB, GAR1, GATAD1,GBA, GBE1, GCLC, GCSH, GDI1, GFPT1, GFRA1, GFRA2, GINS1, GINS2, GLCCI1,GLI3, GLIPR2, GLIS3, GLRX2, GLT8D2, GLUL, CML, GMNN, GNAI1, GPAA1,GPATCH2L, GPATCH4, GPI, GPNMB, GPR137C, GPR34, GPRC5B, GPT2, GRAMD1A,GRINA, GRM8, GRWD1, GTF3A, GTPBP6, GTPBP6, H2AFV, H2AFX, H2AFY2, H6PD,HDAC9, HELLS, HGF, HIBCH, HILPDA, HIST1H1B, HIST1H1C, HIST1H1D,HIST1H1E, HIST1H2AB, HIST1H2AG, HIST1H2AH, HIST1H2A1, HIST1H2AJ,HIST1H2AL, HIST1H2AM, HIST1H2BF, HIST1H2BG, HIST1H2BH, HIST1H2B1,HIST1H2BJ, HIST1H2BK, HIST1H2BL, HIST1H2BO, HIST1H3B, HIST1H3D,HIST1H3F, HIST1H3G, HIST1H3H, HIST1H4B, HIST1H4C, HIST1H4D, HIST1H4H,HIST1H41, HIST2H2AA3, HIST2H2AA4, HIST2H2AB, HIST2H2AC, HIST2H2BE,HIST2H2BF, HIST2H3A, HIST2H3A, HIST2H3D, HIST2H4A, HIST2H4B, HIST3H2A,HIST3H2BB, HJURP, HK2, HLTF, HMGB3, HMGCS1, HMGCS2, HNRNPM, HOXA13,HOXA3, HOXB3, HPCAL1, HS6ST2, HSD17B13, HSF4, HSP90AA1, HSPA13, HSPB3,HSPH1, HTATSF1, HTR7, ID2, ID3, IDH2, ID11, IDO1, IER3, IFI16, IFI44L,IFITM1, IFITM2, IFITM3, IFNGR2, IGF2, IGF2BP3, IGFBP3, IGFBP5, IK,IL13RA1, IL13RA2, IL1R1, IL1RAP, IL20RB, IL32, IL6, INAFM1, INHBB,INSIG2, IRF9, ISY1, ITFG2, ITGA11, ITGA2, ITGA3, ITGA4, ITGA5, ITGA6,ITGA8, ITGAX, ITGB3, ITGB5, ITGB6, ITGBL1, ITM2C, ITPKB, JAK2, JAK2,JUN, KAZALD1, KCNQ3, KCTD11, KDM4C, KDM5C, KEAP1, KIAA0101, KIAA1456,KIF11, KIF14, KIF15, KIF15, KIF15, KIF15, KIF15, KIF18A, KIF20A, KIF22,KIF23, KIF2C, KIF4A, KIFC1, KLF10, KLF9, KLHL4, KNSTRN, KNTC1, KPNA2,KPTN, KRT17, KRT81, KYNU, LACTB, LAMA1, LAMB1, LAMTOR4, LANCL2, LBH,LEF1, LEFTY2, LHX8, LIF, LIFR, LIMCH1, LINC00473, LINGO2, LMAN1, LMBR1L,LMNB1, LMNB2, LMNTD2, LOC100130880, LOX, LPAR6, LPCAT1, LPXN, LRIG3,LRP1, LRRC1, LRRC15, LRRC17, LRRC23, LRRC8C, LRRTM4, LRRTM4, LSAMP,LSG1, LSM3, LSM5, LUZP1, LY6E, LYPD6B, MAGEA1, MAP1LC3C, MAP2K6,MAP3K7CL, MAP9, MAPK14, MAPK1IP1L, MAPK3, MAPRE3, MARS, MASP1, MATN2,MBOAT7, MCAT, MCFD2, MCM2, MCM3, MCM4, MCM5, MCM6, MCM7, MCM8, MCOLN1,MCTP2, MDH1B, MECOM, MEF2A, MEIS2, MELK, METTL15, MFAP3L, MFSD1, MFSD10,MGAT5, MGST3, MILR1, MIR99AHG, MK167, MMAB, MMD, MMP13, MMP3, MNS1,MOCOS, MOCS2, MOGS, MORF4L2, MOSPD2, MPI, MPP7, MPPED2, MPRIP, MRPL3,MRPL51, MRPL57, MRPS11, MSANTD2, MSH2, MT1B, MT1G, MT1IP, MT1L, MT1X,MT2A, MTCH2, MTERF3, MTHFD1, MTIF2, MTPAP, MX1, MYADM, MYBL2, MYLK,MYO6, MYO6, NAGK, NALCN, NAMPT, NANOS1, NAP1L1, NAPA, NASP, NCAM1,NCAPD2, NCAPG, NCAPH, NCK1, NCKAP5, NCL, NCOA4, NCOA7, ND4L, NDC80,NDNF, NDRG1, NDUFA4L2, NDUFS6, NDUFS8, NEIL3, NETO2, NEU1, NEXN, NFAT5,NFE2, NFE2L1, NFKB2, NFKBIA, NFYB, NHEJ1, NHP2, NMI, NOL3, NPIPA1,NPIPA5, NPIPA7, NPIPA7, NPIPA8, NR2C1, NR2F1, NR4A1, NSDHL, NSMAF,NSUN4, NUAK1, NUSAP1, NXPH4, NYAP2, OAS1, OAS2, OASL, OCIAD2, ODC1, OGN,OGT, OLA1, OLFML2B, OLFML3, OR8B12, ORAI3, ORC1, ORC6, OSBPL3, OSGEP,OSMR, OXCT1, P4HA1, P4HA2, PABPC4, PAFAH1B3, PAK1IP1, PAN2, PAQR6,PARD3B, PARM1, PARP14, PCDH10, PCF11, PCMTD1, PCNA, PCNX, PCP4, PCYOX1L,PDE10A, PDE4B, PDE5A, PDGFD, PDGFRA, PDIA4, PDK1, PDLIM5, PELI1, PELO,PEPD, PFKFB4, PFKP, PGAM1, PGK1, PHF19, PHLDA1, PIDD1, PIF1, PIK3R3,PITPNM1, PITX1, PLA2G6, PLACE, PLAGL1, PLAT, PLAU, PLD1, PLD1, PLEKHA2,PLEKHG1, PLEKHS1, PLIN2, PLK4, PLN, PLOD1, PLOD2, PLOD3, PLPP3, PLPP4,PLSCR1, PLXDC2, PLXNC1, PMEPA1, PMM2, PNPLA2, PNPLA6, PNRC1, PODXL,POLQ, POLR1E, POLR2J4, POLR3D, POMT1, PON2, POSTN, PPARGC1A, PPIL1,PPM1B, PPP1R37, PPP1R7, PPP1R8, PPP3CA, PQBP1, PRADC1, PRC1, PRH1,PRIM1, PRKAA2, PRKAB2, PRKAR1A, PRKDC, PRKG1, PROCR, PROZ, PRR4, PRRC2B,PRRT1, PRUNE2, PSAT1, PSD3, PSMA2, PSMB1, PSMD1, PSMD2, PSMD3, PSMD9,PSMG1, PSMG2, PTAR1, PTCHD1, PTGES, PTGES3L-AARSD1, PTGR2, PTGS2,PTPMT1, PTPN13, PTPRG, PTPRM, PTPRN2, PUS7L, PVRL2, QRICH2, RAB27A,RAB33B, RAB7B, RABEP2, RABGGTA, RAD51, RAD51AP1, RAD51C, RALGAPA2,RALGPS2, RANBP3L, RASA4, RASL11A, RBL1, RBL2, RBM3, RBM8A, RBPMS, RCN3,REC8, RECQL4, RELA, REPS1, RFC4, RFPL4A, RGL2, RGS10, RGS18, RGS2, RMI2,RNF144A, RNF145, RNF213, RNF24, RNPEP, RORA, RP11-307P5.1, RPP21, RPP30,RPP40, RPS26, RPS26, RPS6KA3, RRAGC, RRAS, RRBP1, RRM1, RRM2, RTKN2,RTN3, RUNX2, RWDD1, S100A10, SAFB2, SAMD15, SAMD5, SAMD8, SAT1, SATB2,SBNO2, SCAMP3, SCARA3, SCN9A, SCOC, SCRIB, SDC4, SEC14L2, SEC23B,SECISBP2L, SEL1L3, SEMA3C, SEMA4B, SEMA6D, SERHL2, SERINC5, SERPINA3,SETD5, SF3B1, SFR1, SFRP4, SGIP1, SGK1, SGOL2, SGSH, SH3BGRL3, SH3BP2,SHB, SHC1, SHC4, SHCBP1, SHISA5, SHMT1, SIDT2, SIGMAR1, SKA2, SLC14A1,SLC16A1, SLC16A1, SLC16A3, SLC16A4, SLC16A6, SLC1A3, SLC1A5, SLC20A1,SLC25A19, SLC25A36, SLC25A37, SLC26A11, SLC29A1, SLC29A4, SLC2A1,SLC2A14, SLC2A3, SLC35F5, SLC37A3, SLC43A2, SLC4A4, SLC6A6, SLC7A5,SLCO4A1, SLFN5, SLIT2, SLITRK2, SLPI, SMAD7, SMAD9, SMAGP, SMC3, SMIM3,SMOX, SMPD1, SMPDL3A, SNAI1, SNAPC3, SNED1, SNRNP25, SNRPF, SNX2, SNX33,SOBP, SOCS4, SOCS5, SORT1, SOST, SPC24, SPC25, SPDL1, SPOCD1, SPON2,SPP1, SPRY1, SPRY3, SPRY3, SPRY4, SQLE, SRM, SRPX2, SRRT, SSBP2,ST8SIA4, STAG3L4, STC1, STC2, STEAP1B, STEAP2, STEAP3, STIL, STK11IP,STRA6, STXBP5L, SURF4, SURF4, SURF4, SURF4, SUV39H1, SVIP, SYNC, SYNJ2,SYT14, SYTL2, TACC3, TADA3, TAF9, TAF9B, TAGLN2, TANGO6, TAPBP, TAS2R31,TBC1D1, TBC1D28, TBC1D31, TBL1X, TBXAS1, TCEAL2, TCEAL4, TCF19, TCHP,TCP1, TDO2, TEX264, TFAP2A, TFAP2C, TFPI, TFRC, TGFA, TGFB2, THTPA,TIMELESS, TIMM10, TIMP1, TIMP3, TIPARP, TM2D2, TM4SF1, TM9SF4, TMED4,TMED7-TICAM2, TMEM100, TMEM160, TMEM182, TMEM2, TMEM2, TMEM230, TMEM30A,TMEM39A, TMEM70, TMEM97, TMEM98, TMEM99, TMPO, TMSB15A, TMUB1,TNFRSF10B, TNFRSF1A, TNFRSF9, TNFSF10, TOE1, TOMM34, TOP2A, TOR3A, TP63,TPBG, TPCN1, TPM1, TPMT, TPX2, TRAPPC2L, TRAPPC4, TRAPPC5, TRIB2, TRIB3,TRIM22, TRIM25, TRIM36, TRIMS, TRIP10, TRIP13, TRIT1, TRMO, TROAP,TSPAN9, TSR2, TSR3, TTC25, TTC37, TTLL12, TUBG2, TVP23C, TWISTNB, TXN,TXNIP, TYMS, U2AF1, UBE2C, UBR7, UGGT2, UHRF1, UMPS, UNC93B1, UNG, USP3,VAT1, VCAM1, VCAN, VGF, VOPP1, VPS11, VRK1, VWA5A, WARS, WDR27, WDR34,WDR60, WDR62, WDR76, WDR90, WNT2B, WNT5B, WSB1, XBP1, XRCC2, XRCC3,XRCC6BP1, YEATS4, YIF1A, YY1AP1, ZBED6, ZBTB25, ZC4H2, ZDHHC15, ZDHHC4,ZNF160, ZNF326, ZNF358, ZNF382, ZNF395, ZNF414, ZNF511, ZNF512B, ZNF521,ZNF529-AS1, ZNF532, ZNF570, ZNF667, ZNF682, ZNF692, ZNF777, ZNF785,ZNF830, ZNF92, ZWILCH and ZWINT.

Genes regulated more than 2-fold with a FDR<0.1 following treatment withCompound #106 full 2′oMe: AARS, ABCA1, ABLIM1, ACAT2, ACSL5, ADAM9,ADAMTS16, ADAMTS19, ADAMTSL4, ADGRA2, ADRBK1, ADRM1, ADSSL1, AGPS, AGRN,AGT, AHNAK, AHNAK2, AHR, AJAP1, AK7, AKAP12, AKAP6, AKR1C2, AKR1C3,ALCAM, ALDH1L2, ALDH3A1, ALDOC, ALPK2, ALYREF, AMTN, ANK3, ANKRD44,ANPEP, ANTXR2, AOAH, AP4S1, APCDD1, AQP1, ARHGAP11B, ARHGDIB, ARHGEF2,ARL15, ARMC6, ARRDC3, ARRDC4, ARSG, ASPN, ATAD2, ATHL1, ATP13A2,ATP6AP1L, ATP6V1C1, ATXN1, AURKB, BANF1, BCAR3, BCAT1, BCL6, BCO1, BDNF,BEX1, BLID, BMP5, BNC2, BNIP3, BSG, BST2, BTAF1, BTG2, BTG3, BUB1,BUB1B, C10orf107, C14orf1, C14orf132, C1QTNF3, C3orf14, C3orf58, C4A,C4B, C8orf4, C9orf43, C9orf50, CA12, CA9, CACNG4, CALCB, CAMK4, CARS,CASK, CASP4, CBFA2T3, CCDC102B, CCDC34, CCNA2, CCPG1, CD24, CD55, CD82,CD96, CDC45, CDC6, CDCA3, CDCA5, CDCA8, CDH6, CDK1, CEBPG, CENPF, CENPI,CENPM, CENPN, CENPU, CEP128, CFH, CFI, CHAC1, CHEK1, CHL1, CHMP1B,CHRNA1, CHRNA9, CHST15, CLDND1, CLEC2B, CLIC2, CLIC5, CLMN, CLSTN2,CMKLR1, CMTM3, CNPPD1, CNTNAP1, CNTNAP3, CNTNAP3B, CNTNAP3B, CNTNAP3P2,COBLL1, COL1A1, COL3A1, COL5A2, COLEC12, CORIN, CP, CPA4, CSF1,CSGALNACT1, CSGALNACT2, CSNK1E, CTBP1, CTBS, CTH, CTNS, CTSC, CXADR,CXCL14, CXCL3, CXCL8, CYP51A1, CYTH3, DACT1, DACT1, DBI, DBN1, DDIT4,DDX39A, DDX58, DDX60, DECR1, DEPTOR, DET1, DGKD, DGKD, DGKD, DGKD, DGKD,DHCR24, DHCR7, DHFR, DHFR, DHRS3, DHX58, DLG3, DLGAP5, DLX1, DNAH5,DNAJB1, DOCK10, DPT, DPYSL3, DSEL, DSN1, DUSP10, DUSP6, EBP, EEPD1,EFEMP2, EFTUD1, EGLN3, EID1, EIF2AK2, ELAVL2, EMP1, ENC1, ENGASE, ENO1,ENO2, ENPP2, ENTPD4, EPAS1, ERICH1, ERO1A, ERRFI1, ETV1, EXO1, EXT1,EXT1, F3, FAM111A, FAM111B, FAM118B, FAM13A, FAM13C, FAM155A, FAM155A,FAM161A, FAM162A, FAM198B, FAM20C, FAM46A, FAM83D, FANCI, FAP, FAS,FBLN5, FBN1, FBXO32, FGF7, FJX1, FLOT1, FN1, FOXF2, FOXM1, FSTL1, FSTL4,FUT11, GABRE, GADD45A, GATAD1, GBE1, GCLC, GDF15, GDI1, GFRA1, GINS1,GINS2, GLRX, GLT8D2, GLUL, GMFG, GNAI1, GNPDA1, GPC4, GPCPD1, GPI,GPNMB, GPRC5B, GPS2, GPT2, GPX3, GRIP1, H2AFV, H2AFX, HACE1, HDAC9,HDLBP, HGF, HHAT, HIPK2, HIST1H1B, HIST1H1C, HIST1H1D, HIST1H1E,HIST1H2AG, HIST1H2AH, HIST1H2A1, HIST1H2AJ, HIST1H2AL, HIST1H2AM,HIST1H2BF, HIST1H2BH, HIST1H2BI, HIST1H2BJ, HIST1H2BK, HIST1H2BL,HIST1H3B, HIST1H3F, HIST1H3G, HIST1H3H, HIST1H4B, HIST1H4C, HIST1H4H,HIST2H2AA3, HIST2H2AA4, HIST2H2AB, HIST2H2AC, HIST2H2BE, HIST2H2BF,HIST2H3A, HIST2H3A, HIST2H3D, HIST2H4A, HIST2H4B, HIST3H2BB, HLA-DRA,HMCN1, HMGB3, HMGCR, HMGCS1, HMGN2, HNRNPM, HOXA3, HPCAL1, HS6ST2,HSD17B10, HSD17B13, HSF4, HSP90B1, HSPB3, HTR7, ID3, ID11, IDO1, IER3,IF116, IF127, IF144, IF144L, IF16, IFITM1, IFITM2, IFITM3, IGF1, IGFBP3,IGFBP5, IL13RA1, IL13RA2, IL1R1, IL20RB, IL6, IL7R, ILF2, INAFM1, INHBA,INHBB, INSIG1, INSIG2, IRF9, ITGA11, ITGA2, ITGA5, ITGA6, ITGA8, ITGAX,ITGB6, ITGBL1, ITPKB, JAK2, JUN, KBTBD11, KCNH1, KCNQ3, KIAA0101,KIAA1456, KIF11, KIF15, KIF15, KIF15, KIF20A, KIF22, KIF23, KIF26B,KIF2C, KIF4A, KIFC1, KIRREL3, KPNA2, KRT17, KRTAP9-3, KYNU, LACTB,LAMB1, LBH, LEF1, LEFTY1, LEMD1, LEPR, LFNG, LGR4, LIF, LIMCH1,LINC00473, LINC00663, LINC01565, LINGO2, LITAF, LMAN1, LMNB1, LMNB2,LOX, LPAR6, LPCAT1, LRIG3, LRRC15, LRRC23, LRRN1, LRRTM4, LSAMP, LSS,LST1, LXN, LY6E, LY6E, LYPD6B, MAP1LC3C, MAP2K6, MAP3K5, MAP3K7CL,MASP1, MB21D2, MCM2, MCM3, MCM4, MCM5, MCOLN1, MCTP2, MECOM, MEIS2,MELK, MERTK, MET, MFAP2, MFAP3L, MFAP4, MFSD10, MGLL, MGP, MILR1,MIR99AHG, MK167, MMD, MMP13, MOCOS, MPI, MPP7, MPPED2, MSC, MSH2, MT1X,MTFR2, MTHFD1, MTIF2, MX1, MX2, MYBL2, MYLK, MYO5B, MYO6, NAMPT, NANOS1,NBL1, NBN, NCAM1, NCAPD2, NCAPG, NCKAP1, NCOA7, NDC80, NDNF, NDOR1,NDUFA4L2, NES, NEXN, NFE2, NFKBIA, NKAP, NNT, NOL3, NPAS2, NPIPA1,NPIPA5, NPIPA7, NPIPA8, NQO1, NR2F1, NREP, NTM, NUAK1, NUCB2, NUDT22,NUSAP1, NXPH4, NYAP2, OAS1, OAS2, OBFC1, OLFM1, OLFML2A, OLFML2B,OLFML3, OR5H1, OSBPL3, OSGEP, OSMR, OXCT1, P2RX7, P4HA1, PABPC1,PABPC1L2A, PADI3, PADI3, PAN2, PARM1, PARP1, PARP14, PARP9, PAX9,PCDH10, PCNA, PCNX, PCP4, PDE10A, PDE5A, PDGFD, PDGFRA, PDIK1L, PDK1,PDK2, PDLIM5, PEPD, PFKFB4, PFKP, PGK1, PHLDA1, PIDD1, PIK3R3, PITX1,PKD1, PLACE, PLAT, PLAU, PLD1, PLD1, PLIN2, PLK1, PLK4, PLOD1, PLPP3,PLPP4, PLSCR1, PLXDC2, PMEPA1, PNPLA3, POFUT2, POLD2, POLR1E, POLR2J4,POSTN, POU6F1, PPARG, PPARGC1A, PPP1CC, PRC1, PREX2, PRICKLE1, PRIM1,PRKAA2, PRKD1, PROCR, PRR11, PRSS12, PRUNE2, PSD3, PSG4, PTCH1, PTCHD1,PTGES, PTGS2, PTPN13, PTPRM, PVRL2, PXDC1, PYROXD1, RAB27A, RAB43,RACGAP1, RAD54L, RALGAPA2, RANBP3L, RAP2B, RASL11A, RASL11B, RBL2, RBM3,RBPMS, RCN3, REC8, RELB, RGS10, RGS18, RGS2, RHOJ, RNF145, RNF217,RNFT2, RORA, RPS6KA3, RRAGC, RRM1, RTKN2, RUNX2, SAMD15, SAMD8, SAT1,SATB2, SBNO2, SC5D, SDC4, SDR42E1, SECISBP2L, SEL1L3, SEMA4B, SERINC5,SERPINB1, SERPINE2, SERTAD4, SESN3, SFRP4, SGIP1, SGK1, SGOL1, SGSH,SHC1, SHC4, SHCBP1, SHISA5, SHMT1, SIDT2, SIX1, SLC14A1, SLC16A3,SLC16A4, SLC16A6, SLC1A3, SLC20A1, SLC25A37, SLC29A1, SLC29A4, SLC2A14,SLC2A3, SLC39A8, SLC44A4, SLC4A4, SLC50A1, SLC7A5, SLC9A3R2, SLCO1C1,SLCO4A1, SLFN5, SLIT2, SLITRK2, SLPI, SMAD9, SNAI1, SNAP25, SNAPC1,SNX8, SORBS2, SORT1, SPAG4, SPC24, SPC25, SPDL1, SPECC1, SPOCD1, SPP1,SPRY1, SSBP2, ST8SIA4, STARD4, STAT1, STC1, STC2, STEAP2, STEAP3, STMN1,SULT1E1, SYNC, SYNGR1, SYNM, SYT14, TACC3, TAF9B, TBC1D2, TBC1D3L,TBL1X, TDO2, TET3, TFAP2C, TFB1M, TFPI, TFRC, TGFB2, TIMELESS, TIMP1,TIMP3, TIPARP, TK1, TLR3, TM4SF1, TMCO4, TMEM100, TMEM140, TMEM189,TMEM19, TMEM2, TMEM255A, TMEM257, TMEM97, TNC, TNFRSF10B, TNFRSF9,TNFSF10, TOB1, TOP2A, TP63, TPBG, TPM1, TPM2, TPX2, TRAPPC2L, TRIB2,TRIB3, TRIM36, TRIM49C, TSPAN2, TSPAN9, TUBA1A, TVP23C, TXK, TXNIP,TYMS, UAP1L1, UBR7, UHRF1, VASH2, VCAM1, VCAN, VEGFA, VGLL2, VWA5A,WARS, WDR60, WDR62, WDR76, WFDC3, WFS1, WNT2B, WSB1, XBP1, XRCC2, YARS,YIF1A, ZBTB25, ZFP36L2, ZNF395, ZNF521, ZNF667, ZNF804A and ZNF814.

Genes regulated more than 2-fold with a FDR<0.1 following treatment withCompound #106 full 2′MOE: ACAT2, ADI1, ARRDC4, CCPG1, CDCA5, COL3A1, CP,CXCL8, EFEMP2, ENC1, FANCD2, FBN1, HIST1H1B, HIST1H2AG, HIST1H2A1,HIST1H2AL, HIST1H2BA, HIST1H3B, HIST2H2AA4, HIST2H2BF, HIST3H2BB, HSF4,IF144L, IF16, IGFBP3, KHDC1, KIF20A, LEF1, LOX, LY6E, MGAT4C, MMP3, MX1,NDNF, NDUFA4L2, NUSAP1, PDGFD, PHLDA1, PTX3, RGS18, SFRP4, TPBG andVCAN.

Example 13

H4 neuroglioma cells seeded in 96 well plates 5000 pr well were treatedwith 10 μM final concentration of compounds for 5 days in 200 μL fullgrowth medium. Progranulin expression levels were evaluated in the mediaafter dilution 1:8 by ELISA from Abcam (ab252364) according tomanufactorer's protocol. Progranulins levels were normalized to PBStreated cells and values above >1 therefore indicates an upregulation ofPGRN protein levels. Table 4 list the compounds tested, their sequencesand their corresponding target site on the PGRN mRNA as well as theProgranulin protein expression levels.

Lengthy table referenced here US20230287412A1-20230914-T00001 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20230287412A1-20230914-T00002 Pleaserefer to the end of the specification for access instructions.

LENGTHY TABLES The patent application contains a lengthy table section.A copy of the table is available in electronic form from the USPTO website(https://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20230287412A1).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

1. An antisense oligonucleotide progranulin agonist, wherein theantisense oligonucleotide is 8-40 nucleotides in length and comprises acontiguous nucleotide sequence of 8-40 nucleotides in length which arecomplementary to a human progranulin precursor-mRNA (pre-mRNA) or maturemRNA transcript
 2. The antisense oligonucleotide progranulin agonist ofclaim 1, wherein the human progranulin mature mRNA transcript is SEQ IDNO
 1. 3. The antisense oligonucleotide progranulin agonist of claim 1,wherein the human progranulin precursor-mRNA (pre-mRNA) is SEQ ID NO3949.
 4. The antisense oligonucleotide progranulin agonist according toany one of claims 1-3, wherein the contiguous nucleotide sequence is ofa length of at least 12 nucleotides in length.
 5. The antisenseoligonucleotide progranulin agonist according to claim 4, wherein thecontiguous nucleotide sequence is 12-16 or 12-18 nucleotides in length.6. The antisense oligonucleotide progranulin agonist according to claim4, wherein the contiguous nucleotide sequence is 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,36, 37, 38, 39 or 40 nucleotides in length.
 7. The antisenseoligonucleotide progranulin agonist according to any one of claims 1-6,wherein the contiguous nucleotide sequence is the same length as theantisense oligonucleotide.
 8. The antisense oligonucleotide progranulinagonist according to any one of claims 1-7, wherein the contiguousnucleotide sequence is fully complementary to the human progranulinprecursor-mRNA (pre-mRNA) or mature mRNA transcript.
 9. The antisenseoligonucleotide progranulin agonist according to any one of claims 1-8,wherein the contiguous nucleotide sequence is complementary to a 5′UTRregion of a human progranulin mature mRNA transcript.
 10. The antisenseoligonucleotide progranulin agonist according to claim 9, wherein thecontiguous nucleotide sequence is complementary to SEQ ID NO 2, SEQ IDNO 689, SEQ ID NO 683, or a sequence selected from the group consistingof SEQ ID NO 343-586.
 11. The antisense oligonucleotide progranulinagonist according to any one of claims 1-9, wherein the contiguousnucleotide sequence is complementary to nucleotides 38-246 of SEQ IDNO
 1. 12. The antisense oligonucleotide progranulin agonist according toany one of claims 1-9, wherein the contiguous nucleotide sequence isfully complementary to SEQ ID NO 2, or SEQ ID NO
 689. 13. The antisenseoligonucleotide progranulin agonist according to any one of claims 1-9,wherein the contiguous nucleotide sequence is fully complementary to asequence selected from the group consisting of SEQ ID NO 568, SEQ ID NO571, SEQ ID NO 575, SEQ ID NO 576, SEQ ID NO 577, SEQ ID NO 578, SEQ IDNO 584 & SEQ ID NO
 586. 14. The antisense oligonucleotide progranulinagonist according to any one of claims 1-13, wherein the contiguousnucleotide sequence is a sequence selected from the group consisting ofSEQ ID NO 3-342, or at least 8 or at least 10 contiguous nucleotidesthereof.
 15. The antisense oligonucleotide progranulin agonist accordingto any one of claims 1-14, wherein the contiguous nucleotide sequence isselected from SEQ ID NO 105, SEQ ID NO 106, SEQ ID NO 110, SEQ ID NO113, SEQ ID NO 114, SEQ ID NO 231 and SEQ ID NO 241 or at least 8 or atleast 10 contiguous nucleotides thereof.
 16. The antisenseoligonucleotide progranulin agonist according to any one of claims 1-8,wherein contiguous nucleotide sequence is complementary to a 3′UTRregion of a human progranulin mature mRNA transcript.
 17. The antisenseoligonucleotide progranulin agonist according to claim 16, wherein thecontiguous nucleotide sequence is complementary to SEQ ID NO 684, SEQ IDNO 685, SEQ ID NO 686, SEQ ID NO 687, SEQ ID NO 688, or a sequenceselected from the group consisting of SEQ ID NO 587-682.
 18. Theantisense oligonucleotide progranulin agonist according to claim 16,wherein the contiguous nucleotide sequence is complementary tonucleotides 2039-2346 of SEQ ID NO
 1. 19. The antisense oligonucleotideprogranulin agonist according to any one of claims 16-18 wherein thecontiguous nucleotide sequence is fully complementary to a sequenceselected from the group consisting of SEQ ID NO 684, SEQ ID NO 685, SEQID NO 686, SEQ ID NO 687, and SEQ ID NO
 688. 20. The antisenseoligonucleotide progranulin agonist according to any one of claims 16-19wherein the contiguous nucleotide sequence is fully complementary to asequence selected from the group consisting of SEQ ID NO 607, SEQ ID NO608, SEQ ID NO 609, SEQ ID NO 610, SEQ ID NO 611, SEQ ID NO 612, SEQ IDNO 619, SEQ ID NO 620, SEQ ID NO 633, SEQ ID NO 640, SEQ ID NO 641, SEQID NO 645, SEQ ID NO 651, and SEQ ID NO
 652. 21. The antisenseoligonucleotide progranulin agonist according to any one of claims16-20, wherein the contiguous nucleotide sequence is selected from SEQID NO 267, SEQ ID NO 268, SEQ ID NO 269, SEQ ID NO 270, SEQ ID NO 271,SEQ ID NO 272, SEQ ID NO 279, SEQ ID NO 280, SEQ ID NO 293, SEQ ID NO300, SEQ ID NO 301, SEQ ID NO 305, SEQ ID NO 311, and SEQ ID NO 312, orat least 8 or at least 10 contiguous nucleotides thereof.
 22. Theantisense oligonucleotide progranulin agonist according to any one ofclaims 1-8, wherein the contiguous nucleotide sequence is complementaryto a sequence selected from the group consisting of SEQ ID NO 2040-3386.23. The antisense oligonucleotide progranulin agonist according to claim22, wherein the contiguous nucleotide sequence is complementary to asequence selected from the group consisting of SEQ ID 2321, SEQ ID 2322,SEQ ID 2324, SEQ ID 2328, SEQ ID 2329, SEQ ID 2331, SEQ ID 2334, SEQ ID2335, SEQ ID 2336, SEQ ID 2337, SEQ ID 2338, SEQ ID 2339, SEQ ID 2340,SEQ ID 2341, SEQ ID 2342, SEQ ID 2345, SEQ ID 2346, SEQ ID 2347, SEQ ID2348, SEQ ID 2349, SEQ ID 2350, SEQ ID 2351, SEQ ID 2352, SEQ ID 2353,SEQ ID 2354, SEQ ID 2355, SEQ ID 2356, SEQ ID 2357, SEQ ID 2358, SEQ ID2359, SEQ ID 2360, SEQ ID 2361, SEQ ID 2362, SEQ ID 2364, SEQ ID 2365,SEQ ID 2366, SEQ ID 2367, SEQ ID 2368, SEQ ID 2369, SEQ ID 2370, SEQ ID2371, SEQ ID 2372, SEQ ID 2373, SEQ ID 2374, SEQ ID 2375, SEQ ID 2376,SEQ ID 2377, SEQ ID 2378, SEQ ID 2379, SEQ ID 2380, SEQ ID 2381, SEQ ID2384, SEQ ID 2386, SEQ ID 2387, SEQ ID 2388, SEQ ID 2389, SEQ ID 2390,SEQ ID 2392, SEQ ID 2393, SEQ ID 2394, SEQ ID 2395, SEQ ID 2396, SEQ ID2397, SEQ ID 2398, SEQ ID 2399, SEQ ID 2400, SEQ ID 2401, SEQ ID 2403,SEQ ID 2404, SEQ ID 2405, SEQ ID 2406, SEQ ID 2407, SEQ ID 2408, SEQ ID2410, SEQ ID 2411, SEQ ID 2413, SEQ ID 2414, SEQ ID 2415, SEQ ID 2416,SEQ ID 2418, SEQ ID 2419, SEQ ID 2421, SEQ ID 2424, SEQ ID 2425, SEQ ID2426, SEQ ID 2427, SEQ ID 2428, SEQ ID 2429, SEQ ID 2430, SEQ ID 2431,SEQ ID 2432, SEQ ID 2433, SEQ ID 2434, SEQ ID 2435, SEQ ID 2436, SEQ ID2437, SEQ ID 2438, SEQ ID 2439, SEQ ID 2440, SEQ ID 2441, SEQ ID 2442,SEQ ID 2443, SEQ ID 2444, SEQ ID 2445, SEQ ID 2446, SEQ ID 2447, SEQ ID2448, SEQ ID 2449, SEQ ID 2450, SEQ ID 2451, SEQ ID 2452, SEQ ID 2453,SEQ ID 2454, SEQ ID 2455, SEQ ID 2456, SEQ ID 2457, SEQ ID 2458, SEQ ID2459, SEQ ID 2460, SEQ ID 2461, SEQ ID 2462, SEQ ID 2463, SEQ ID 2464,SEQ ID 2465, SEQ ID 2466, SEQ ID 2467, SEQ ID 2468, SEQ ID 2469, SEQ ID2470, SEQ ID 2471, SEQ ID 2472, SEQ ID 2473, SEQ ID 2474, SEQ ID 2475,SEQ ID 2476, SEQ ID 2477, SEQ ID 2478, SEQ ID 2479, SEQ ID 2481, SEQ ID2482, SEQ ID 2483, SEQ ID 2484, SEQ ID 2485, SEQ ID 2487, SEQ ID 2489,SEQ ID 2490, SEQ ID 2491, SEQ ID 2492, SEQ ID 2493, SEQ ID 2494, SEQ ID2495, SEQ ID 2496, SEQ ID 2497, SEQ ID 2498, SEQ ID 2499, SEQ ID 2501,SEQ ID 2502, SEQ ID 2503, SEQ ID 2504, SEQ ID 2505, SEQ ID 2506, SEQ ID2507, SEQ ID 2508, SEQ ID 2509, SEQ ID 2510, SEQ ID 2511, SEQ ID 2512,SEQ ID 2513, SEQ ID 2514, SEQ ID 2515, SEQ ID 2516, SEQ ID 2518, SEQ ID2519, SEQ ID 2520, SEQ ID 2521, SEQ ID 2522, SEQ ID 2523, SEQ ID 2524,SEQ ID 2525, SEQ ID 2526, SEQ ID 2527, SEQ ID 2528, SEQ ID 2531, SEQ ID2533, SEQ ID 2534, SEQ ID 2535, SEQ ID 2536, SEQ ID 2537, SEQ ID 2538,SEQ ID 2540, SEQ ID 2541, SEQ ID 2542, SEQ ID 2544, SEQ ID 2546, SEQ ID2547, SEQ ID 2549, SEQ ID 2550, SEQ ID 2551, SEQ ID 2553, SEQ ID 2554,SEQ ID 2555, SEQ ID 2556, SEQ ID 2557, SEQ ID 2560, SEQ ID 2561, SEQ ID2562, SEQ ID 2563, SEQ ID 2565, SEQ ID 2566, SEQ ID 2567, SEQ ID 2572,SEQ ID 2573, SEQ ID 2574, SEQ ID 2575, SEQ ID 2576, SEQ ID 2577, SEQ ID2578, SEQ ID 2579, SEQ ID 2580, SEQ ID 2581, SEQ ID 2582, SEQ ID 2583,SEQ ID 2584, SEQ ID 2585, SEQ ID 2586, SEQ ID 2588, SEQ ID 2589, SEQ ID2590, SEQ ID 2591, SEQ ID 2592, SEQ ID 2593, SEQ ID 2594, SEQ ID 2595,SEQ ID 2596, SEQ ID 2597, SEQ ID 2598, SEQ ID 2599, SEQ ID 2601, SEQ ID2602, SEQ ID 2603, SEQ ID 2604, SEQ ID 2606, SEQ ID 2610, SEQ ID 2613,SEQ ID 2614, SEQ ID 2615, SEQ ID 2619, SEQ ID 2622, SEQ ID 2623, SEQ ID2624, SEQ ID 2625, SEQ ID 2626, SEQ ID 2627, SEQ ID 2628, SEQ ID 2629,SEQ ID 2630, SEQ ID 2631, SEQ ID 2632, SEQ ID 2633, SEQ ID 2634, SEQ ID2635, SEQ ID 2636, SEQ ID 2637, SEQ ID 2638, SEQ ID 2639, SEQ ID 2640,SEQ ID 2641, SEQ ID 2642, SEQ ID 2643, SEQ ID 2644, SEQ ID 2645, SEQ ID2646, SEQ ID 2647, SEQ ID 2648, SEQ ID 2649, SEQ ID 2650, SEQ ID 2651,SEQ ID 2652, SEQ ID 2653, SEQ ID 2654, SEQ ID 2655, SEQ ID 2656, SEQ ID2658, SEQ ID 2659, SEQ ID 2660, SEQ ID 2661, SEQ ID 2662, SEQ ID 2663,SEQ ID 2664, SEQ ID 2665, SEQ ID 2666, SEQ ID 2667, SEQ ID 2668, SEQ ID2669, SEQ ID 2670, SEQ ID 2671, SEQ ID 2672, SEQ ID 2673, SEQ ID 2674,SEQ ID 2675, SEQ ID 2676, SEQ ID 2677, SEQ ID 2678, SEQ ID 2679, SEQ ID2680, SEQ ID 2681, SEQ ID 2682, SEQ ID 2683, SEQ ID 2684, SEQ ID 2685,SEQ ID 2686, SEQ ID 2687, SEQ ID 2688, SEQ ID 2689, SEQ ID 2690, SEQ ID2691, SEQ ID 2693, SEQ ID 2694, SEQ ID 2695, SEQ ID 2696, SEQ ID 2697,SEQ ID 2698, SEQ ID 2699, SEQ ID 2700, SEQ ID 2701, SEQ ID 2702, SEQ ID2703, SEQ ID 2704, SEQ ID 2705, SEQ ID 2706, SEQ ID 2707, SEQ ID 2708,SEQ ID 2709, SEQ ID 2710, SEQ ID 2711, SEQ ID 2712, SEQ ID 2713, SEQ ID2714, SEQ ID 2715, SEQ ID 2716, SEQ ID 2717, SEQ ID 2718, SEQ ID 2719,SEQ ID 2720, SEQ ID 2721, SEQ ID 2722, SEQ ID 2723, SEQ ID 2726, SEQ ID2727, SEQ ID 2728, SEQ ID 2729, SEQ ID 2730, SEQ ID 2733, SEQ ID 2734,SEQ ID 2735, SEQ ID 2736, SEQ ID 2737, SEQ ID 2738, SEQ ID 2739, SEQ ID2740, SEQ ID 2741, SEQ ID 2742, SEQ ID 2743, SEQ ID 2744, SEQ ID 2745,SEQ ID 2746, SEQ ID 2747, SEQ ID 2748, SEQ ID 2749, SEQ ID 2750, SEQ ID2751, SEQ ID 2752, SEQ ID 2753, SEQ ID 2754, SEQ ID 2755, SEQ ID 2756,SEQ ID 2757, SEQ ID 2758, SEQ ID 2759, SEQ ID 2760, SEQ ID 2761, SEQ ID2762, SEQ ID 2763, SEQ ID 2764, SEQ ID 2765, SEQ ID 2766, SEQ ID 2767,SEQ ID 2768, SEQ ID 2769, SEQ ID 2770, SEQ ID 2771, SEQ ID 2772, SEQ ID2773, SEQ ID 2774, SEQ ID 2775, SEQ ID 2815, SEQ ID 2816, SEQ ID 2817,SEQ ID 2818, SEQ ID 2819, SEQ ID 2820, SEQ ID 2821, SEQ ID 2822, SEQ ID2823, SEQ ID 2824, SEQ ID 2825, SEQ ID 2826, SEQ ID 2827, SEQ ID 2828,SEQ ID 2829, SEQ ID 2830, SEQ ID 2831, SEQ ID 2832, SEQ ID 2833, SEQ ID2834, SEQ ID 2835, SEQ ID 2836, SEQ ID 2837, SEQ ID 2838, SEQ ID 2839,SEQ ID 2840, SEQ ID 2841, SEQ ID 2842, SEQ ID 2843, SEQ ID 2844, SEQ ID2845, SEQ ID 2847, SEQ ID 2848, SEQ ID 2849, SEQ ID 2850, SEQ ID 2851,SEQ ID 2852, SEQ ID 2853, SEQ ID 2854, SEQ ID 2855, SEQ ID 2858, SEQ ID2859, SEQ ID 2860, SEQ ID 2861, SEQ ID 2862, SEQ ID 2863, SEQ ID 2864,SEQ ID 2865, SEQ ID 2866, SEQ ID 2867, SEQ ID 2868, SEQ ID 2869, SEQ ID2870, SEQ ID 2871, SEQ ID 2872, SEQ ID 2873, SEQ ID 2874, SEQ ID 2875,SEQ ID 2876, SEQ ID 2878, SEQ ID 2879, SEQ ID 2880, SEQ ID 2881, SEQ ID2882, SEQ ID 2883, SEQ ID 2884, SEQ ID 2885, SEQ ID 2886, SEQ ID 2887,SEQ ID 2888, SEQ ID 2889, SEQ ID 2890, SEQ ID 2891, SEQ ID 2892, SEQ ID2893, SEQ ID 2894, SEQ ID 2895, SEQ ID 2896, SEQ ID 2897, SEQ ID 2898,SEQ ID 2899, SEQ ID 2900, SEQ ID 2901, SEQ ID 2902, SEQ ID 2903, SEQ ID2904, SEQ ID 2905, SEQ ID 2906, SEQ ID 2907, SEQ ID 2908, SEQ ID 2909,SEQ ID 2910, SEQ ID 2911, SEQ ID 2912, SEQ ID 2913, SEQ ID 2914, SEQ ID2915, SEQ ID 2916, SEQ ID 2917, SEQ ID 2918, SEQ ID 2919, SEQ ID 2920,SEQ ID 2921, SEQ ID 2922, SEQ ID 2923, SEQ ID 2924, SEQ ID 2925, SEQ ID2926, SEQ ID 2927, SEQ ID 2928, SEQ ID 2929, SEQ ID 2930, SEQ ID 2931,SEQ ID 2932, SEQ ID 2934, SEQ ID 2935, SEQ ID 2936, SEQ ID 2937, SEQ ID2938, SEQ ID 2939, SEQ ID 2940, SEQ ID 2941, SEQ ID 2942, SEQ ID 2943,SEQ ID 2944, SEQ ID 2945, SEQ ID 2946, SEQ ID 2947, SEQ ID 2948, SEQ ID2949, SEQ ID 2950, SEQ ID 2951, SEQ ID 2953, SEQ ID 2954, SEQ ID 2955,SEQ ID 2956, SEQ ID 2957, SEQ ID 2958, SEQ ID 2960, SEQ ID 2961, SEQ ID2963, SEQ ID 2964, SEQ ID 2965, SEQ ID 2966, SEQ ID 2967, SEQ ID 2969,SEQ ID 2970, SEQ ID 2971, SEQ ID 2972, SEQ ID 2973, SEQ ID 2974, SEQ ID2975, SEQ ID 2976, SEQ ID 2977, SEQ ID 2978, SEQ ID 2979, SEQ ID 2980,SEQ ID 2981, SEQ ID 2982, SEQ ID 2983, SEQ ID 2984, SEQ ID 2985, SEQ ID3053, SEQ ID 3054, SEQ ID 3055, SEQ ID 3056, SEQ ID 3057, SEQ ID 3058,SEQ ID 3059, SEQ ID 3060, SEQ ID 3061, SEQ ID 3062, SEQ ID 3063, SEQ ID3064, SEQ ID 3065, SEQ ID 3066, SEQ ID 3068, SEQ ID 3069, SEQ ID 3070,SEQ ID 3071, SEQ ID 3072, SEQ ID 3073, SEQ ID 3074, SEQ ID 3075, SEQ ID3076, SEQ ID 3077, SEQ ID 3078, SEQ ID 3079, SEQ ID 3080, SEQ ID 3081,SEQ ID 3082, SEQ ID 3083, SEQ ID 3084, SEQ ID 3085, SEQ ID 3086, SEQ ID3087, SEQ ID 3088, SEQ ID 3089, SEQ ID 3090, SEQ ID 3091, SEQ ID 3092,SEQ ID 3093, SEQ ID 3094, SEQ ID 3095, SEQ ID 3097, SEQ ID 3098, SEQ ID3099, SEQ ID 3100, SEQ ID 3102, SEQ ID 3103, SEQ ID 3104, SEQ ID 3105,SEQ ID 3106, SEQ ID 3107, SEQ ID 3108, SEQ ID 3109, SEQ ID 3110, SEQ ID3112, SEQ ID 3113, SEQ ID 3115, SEQ ID 3116, SEQ ID 3117, SEQ ID 3119,SEQ ID 3120, SEQ ID 3121, SEQ ID 3122, SEQ ID 3123, SEQ ID 3124, SEQ ID3125, SEQ ID 3126, SEQ ID 3127, SEQ ID 3128, SEQ ID 3129, SEQ ID 3130,SEQ ID 3131, SEQ ID 3132, SEQ ID 3133, SEQ ID 3134, SEQ ID 3135, SEQ ID3136, SEQ ID 3137, SEQ ID 3138, SEQ ID 3139, SEQ ID 3140, SEQ ID 3141,SEQ ID 3142, SEQ ID 3143, SEQ ID 3144, SEQ ID 3145, SEQ ID 3146, SEQ ID3147, SEQ ID 3148, SEQ ID 3149, SEQ ID 3150, SEQ ID 3151, SEQ ID 3152,SEQ ID 3153, SEQ ID 3154, SEQ ID 3155, SEQ ID 3156, SEQ ID 3157, SEQ ID3158, SEQ ID 3159, SEQ ID 3160, SEQ ID 3161, SEQ ID 3162, SEQ ID 3163,SEQ ID 3164, SEQ ID 3165, SEQ ID 3166, SEQ ID 3167, SEQ ID 3168, SEQ ID3169, SEQ ID 3170, SEQ ID 3171, SEQ ID 3172, SEQ ID 3173, SEQ ID 3174,SEQ ID 3175, SEQ ID 3176, SEQ ID 3177, SEQ ID 3178, SEQ ID 3179, SEQ ID3180, SEQ ID 3181, SEQ ID 3182, SEQ ID 3183, SEQ ID 3184, SEQ ID 3185,SEQ ID 3186, SEQ ID 3187, SEQ ID 3188, SEQ ID 3189, SEQ ID 3190, SEQ ID3191, SEQ ID 3192, SEQ ID 3193, SEQ ID 3194, SEQ ID 3195, SEQ ID 3196,SEQ ID 3197, SEQ ID 3198, SEQ ID 3199, SEQ ID 3200, SEQ ID 3201, SEQ ID3202, SEQ ID 3203, SEQ ID 3204, SEQ ID 3205, SEQ ID 3206, SEQ ID 3207,SEQ ID 3208, SEQ ID 3209, SEQ ID 3210, SEQ ID 3211, SEQ ID 3212, SEQ ID3213, SEQ ID 3214, SEQ ID 3215, SEQ ID 3216, SEQ ID 3217, SEQ ID 3218,SEQ ID 3219, SEQ ID 3220, SEQ ID 3221, SEQ ID 3222, SEQ ID 3223, SEQ ID3224, SEQ ID 3225, SEQ ID 3226, SEQ ID 3227, SEQ ID 3228, SEQ ID 3229,SEQ ID 3230, SEQ ID 3231, SEQ ID 3232, SEQ ID 3233, SEQ ID 3234, SEQ ID3235, SEQ ID 3236, SEQ ID 3237, SEQ ID 3238, SEQ ID 3239, SEQ ID 3240,SEQ ID 3241, SEQ ID 3242, SEQ ID 3243, SEQ ID 3244, SEQ ID 3245, SEQ ID3246, SEQ ID 3248, SEQ ID 3249, SEQ ID 3250, SEQ ID 3251, SEQ ID 3252,SEQ ID 3253, SEQ ID 3254, SEQ ID 3255, SEQ ID 3256, SEQ ID 3257, SEQ ID3258, SEQ ID 3259, SEQ ID 3260, SEQ ID 3261, SEQ ID 3262, SEQ ID 3263,SEQ ID 3264, SEQ ID 3265, SEQ ID 3266, SEQ ID 3267, SEQ ID 3268, SEQ ID3269, SEQ ID 3270, SEQ ID 3271, SEQ ID 3272, SEQ ID 3273, SEQ ID 3275,SEQ ID 3276, SEQ ID 3277, SEQ ID 3278, SEQ ID 3279, SEQ ID 3280, SEQ ID3282, SEQ ID 3284, SEQ ID 3285, SEQ ID 3286, SEQ ID 3287, SEQ ID 3288,SEQ ID 3289, SEQ ID 3291, SEQ ID 3292, SEQ ID 3293, SEQ ID 3294, SEQ ID3295, SEQ ID 3296, SEQ ID 3297, SEQ ID 3298, SEQ ID 3299, SEQ ID 3300,SEQ ID 3301, SEQ ID 3302, SEQ ID 3303, SEQ ID 3304, SEQ ID 3305, SEQ ID3306, SEQ ID 3307, SEQ ID 3308, SEQ ID 3309, SEQ ID 3310, SEQ ID 3311,SEQ ID 3312, SEQ ID 3313, SEQ ID 3314, SEQ ID 3315, SEQ ID 3316, SEQ ID3317, SEQ ID 3318, SEQ ID 3320, SEQ ID 3321, SEQ ID 3322, SEQ ID 3323,SEQ ID 3324, SEQ ID 3325, SEQ ID 3326, SEQ ID 3327, SEQ ID 3329, SEQ ID3331, SEQ ID 3332, SEQ ID 3333, SEQ ID 3334, SEQ ID 3335, SEQ ID 3336,SEQ ID 3337, SEQ ID 3338, SEQ ID 3339, SEQ ID 3340, SEQ ID 3342, SEQ ID3343, SEQ ID 3344, SEQ ID 3345, SEQ ID 3346, SEQ ID 3347, SEQ ID 3348,SEQ ID 3349, SEQ ID 3350, SEQ ID 3351, SEQ ID 3352, SEQ ID 3353, SEQ ID3354, SEQ ID 3355, SEQ ID 3356, SEQ ID 3357, SEQ ID 3358, SEQ ID 3359,SEQ ID 3360, SEQ ID 3361, SEQ ID 3362, SEQ ID 3363, SEQ ID 3364, SEQ ID3365, SEQ ID 3366, SEQ ID 3367, SEQ ID 3368, SEQ ID 3369, SEQ ID 3370,SEQ ID 3371, SEQ ID 3390, SEQ ID 3391, SEQ ID 3392, SEQ ID 3393, SEQ ID3394, SEQ ID 3395, SEQ ID 3396, SEQ ID 3397, SEQ ID 3398, SEQ ID 3399,SEQ ID 3400, SEQ ID 3401, SEQ ID 3402, SEQ ID 3403, SEQ ID 3404, SEQ ID3405, SEQ ID 3406, SEQ ID 3407, SEQ ID 3408, SEQ ID 3409, SEQ ID 3410,SEQ ID 3411, SEQ ID 3412, SEQ ID 3413, SEQ ID 3414, SEQ ID 3415, SEQ ID3416, SEQ ID 3417, SEQ ID 3418, SEQ ID 3419, SEQ ID 3420, SEQ ID 3421,SEQ ID 3422, SEQ ID 3423, SEQ ID 3424, SEQ ID 3425, SEQ ID 3426, SEQ ID3427, SEQ ID 3428, SEQ ID 3429, SEQ ID 3430, SEQ ID 3431, SEQ ID 3432,SEQ ID 3433, SEQ ID 3434, SEQ ID 3435, SEQ ID 3436, SEQ ID 3437, SEQ ID3438, SEQ ID 3439, SEQ ID 3440, SEQ ID 3441, SEQ ID 3442, SEQ ID 3443,SEQ ID 3444, SEQ ID 3445, SEQ ID 3446, SEQ ID 3447, SEQ ID 3448, SEQ ID3449, SEQ ID 3450, SEQ ID 3451, SEQ ID 3452, SEQ ID 3453, SEQ ID 3454,SEQ ID 3460, SEQ ID 3461, SEQ ID 3464, SEQ ID 3465, SEQ ID 3466, SEQ ID3467, SEQ ID 3468, SEQ ID 3486, SEQ ID 3487, SEQ ID 3488, SEQ ID 3489,SEQ ID 3490, SEQ ID 3491, SEQ ID 3493, SEQ ID 3494, SEQ ID 3496, SEQ ID3497, SEQ ID 3501, SEQ ID 3505, SEQ ID 3508, SEQ ID 3511, SEQ ID 3512,SEQ ID 3516, SEQ ID 3517, SEQ ID 3518, SEQ ID 3521, SEQ ID 3522, SEQ ID3523, SEQ ID 3524, SEQ ID 3525, SEQ ID 3526, SEQ ID 3527, SEQ ID 3528,SEQ ID 3530, SEQ ID 3531, SEQ ID 3532, SEQ ID 3534, SEQ ID 3535, SEQ ID3536, SEQ ID 3538, SEQ ID 3539, SEQ ID 3541, SEQ ID 3542, SEQ ID 3543,SEQ ID 3544, SEQ ID 3546, SEQ ID 3548, SEQ ID 3549, SEQ ID 3550, SEQ ID3552, SEQ ID 3556, SEQ ID 3557, SEQ ID 3558, SEQ ID 3560, SEQ ID 3561,SEQ ID 3566, SEQ ID 3567, SEQ ID 3568, SEQ ID 3569, SEQ ID 3571, SEQ ID3572, SEQ ID 3573, SEQ ID 3574, SEQ ID 3576, SEQ ID 3577, SEQ ID 3578,SEQ ID 3580, SEQ ID 3581, SEQ ID 3584, SEQ ID 3585, SEQ ID 3586, SEQ ID3588, SEQ ID 3590, SEQ ID 3592, SEQ ID 3594, SEQ ID 3595, SEQ ID 3598,SEQ ID 3599, SEQ ID 3600, SEQ ID 3601, SEQ ID 3602, SEQ ID 3603, SEQ ID3605, SEQ ID 3607, SEQ ID 3609, SEQ ID 3610, SEQ ID 3613, SEQ ID 3614,SEQ ID 3615, SEQ ID 3616, SEQ ID 3617, SEQ ID 3621, SEQ ID 3623, SEQ ID3624, SEQ ID 3625, SEQ ID 3626, SEQ ID 3627, SEQ ID 3628, SEQ ID 3629,SEQ ID 3630, SEQ ID 3631, SEQ ID 3632, SEQ ID 3633, SEQ ID 3636, SEQ ID3637, SEQ ID 3638, SEQ ID 3639, SEQ ID 3641, SEQ ID 3642, SEQ ID 3643,SEQ ID 3645, SEQ ID 3647, SEQ ID 3648, SEQ ID 3649, SEQ ID 3651, SEQ ID3654, SEQ ID 3656, SEQ ID 3659, SEQ ID 3660, SEQ ID 3661, SEQ ID 3663,SEQ ID 3664, SEQ ID 3665, SEQ ID 3666, SEQ ID 3670, SEQ ID 3672, SEQ ID3676, SEQ ID 3678, SEQ ID 3679, SEQ ID 3680, SEQ ID 3681, SEQ ID 3682,SEQ ID 3683, SEQ ID 3684, SEQ ID 3685, SEQ ID 3686, SEQ ID 3687, SEQ ID3688, SEQ ID 3689, SEQ ID 3690, SEQ ID 3691, SEQ ID 3692, SEQ ID 3693,SEQ ID 3694, SEQ ID 3695, SEQ ID 3696, SEQ ID 3697, SEQ ID 3698, SEQ ID3699, SEQ ID 3700, SEQ ID 3701, SEQ ID 3702, SEQ ID 3703, SEQ ID 3704,SEQ ID 3705, SEQ ID 3706, SEQ ID 3707, SEQ ID 3708, SEQ ID 3709, SEQ ID3710, SEQ ID 3711, SEQ ID 3712, SEQ ID 3713, SEQ ID 3714, SEQ ID 3715,SEQ ID 3716, SEQ ID 3717, SEQ ID 3718, SEQ ID 3719, SEQ ID 3720, SEQ ID3721, SEQ ID 3722, SEQ ID 3723, SEQ ID 3724, SEQ ID 3725, SEQ ID 3726,SEQ ID 3727, SEQ ID 3729, SEQ ID 3730, SEQ ID 3731, SEQ ID 3732, SEQ ID3733, SEQ ID 3734, SEQ ID 3735, SEQ ID 3736, SEQ ID 3737, SEQ ID 3738,SEQ ID 3739, SEQ ID 3740, SEQ ID 3741, SEQ ID 3742, SEQ ID 3743, SEQ ID3744, SEQ ID 3745, SEQ ID 3746, SEQ ID 3747, SEQ ID 3748, SEQ ID 3749,SEQ ID 3750, SEQ ID 3751, SEQ ID 3752, SEQ ID 3753, SEQ ID 3754, SEQ ID3755, SEQ ID 3774, SEQ ID 3775, SEQ ID 3776, SEQ ID 3777, SEQ ID 3778,SEQ ID 3779, SEQ ID 3780, SEQ ID 3781, SEQ ID 3782, SEQ ID 3783, SEQ ID3784, SEQ ID 3785, SEQ ID 3786, SEQ ID 3787, SEQ ID 3788, SEQ ID 3789,SEQ ID 3790, SEQ ID 3791, SEQ ID 3792, SEQ ID 3793, SEQ ID 3794, SEQ ID3795, SEQ ID 3796, SEQ ID 3797, SEQ ID 3798, SEQ ID 3799, SEQ ID 3800,SEQ ID 3801, SEQ ID 3802, SEQ ID 3803, SEQ ID 3804, SEQ ID 3805, SEQ ID3806, SEQ ID 3807, SEQ ID 3808, SEQ ID 3809, SEQ ID 3810, SEQ ID 3811,SEQ ID 3812, SEQ ID 3813, SEQ ID 3814, SEQ ID 3815, SEQ ID 3816, SEQ ID3817, SEQ ID 3818, SEQ ID 3819, SEQ ID 3820, SEQ ID 3821, SEQ ID 3822,SEQ ID 3823, SEQ ID 3824, SEQ ID 3825, SEQ ID 3826, SEQ ID 3827, SEQ ID3828, SEQ ID 3829, SEQ ID 3830, SEQ ID 3831, SEQ ID 3832, SEQ ID 3833,SEQ ID 3834, SEQ ID 3835, SEQ ID 3836, SEQ ID 3837, SEQ ID 3838, SEQ ID3839, SEQ ID 3840, SEQ ID 3841, SEQ ID 3842, SEQ ID 3844, SEQ ID 3848,SEQ ID 3850, SEQ ID 3851, SEQ ID 3852, SEQ ID 3853, SEQ ID 3867, SEQ ID3868, SEQ ID 3869, SEQ ID 3870, SEQ ID 3871, SEQ ID 3872, SEQ ID 3873,SEQ ID 3874, SEQ ID 3875, SEQ ID 3876, SEQ ID 3877, SEQ ID 3878, SEQ ID3879, SEQ ID 3880, SEQ ID 3881, SEQ ID 3882, SEQ ID 3883, SEQ ID 3884,SEQ ID 3885, SEQ ID 3886, SEQ ID 3887, SEQ ID 3888, SEQ ID 3889, SEQ ID3890, SEQ ID 3891, SEQ ID 3892, SEQ ID 3893, SEQ ID 3894, SEQ ID 3895,SEQ ID 3896, SEQ ID 3897, SEQ ID 3898, SEQ ID 3899, SEQ ID 3900, SEQ ID3901, SEQ ID 3902, SEQ ID 3903, SEQ ID 3904, SEQ ID 3905, SEQ ID 3906,SEQ ID 3907, SEQ ID 3908, SEQ ID 3909, SEQ ID 3910, SEQ ID 3911, SEQ ID3912, SEQ ID 3913, SEQ ID 3914, SEQ ID 3915, SEQ ID 3916, SEQ ID 3917,SEQ ID 3918, SEQ ID 3919, SEQ ID 3920, SEQ ID 3921, SEQ ID 3922, SEQ ID3923, SEQ ID 3924, SEQ ID 3925, SEQ ID 3926, SEQ ID 3927, SEQ ID 3928,SEQ ID 3929, SEQ ID 3930, SEQ ID 3931, SEQ ID 3932, SEQ ID 3933, SEQ ID3934, SEQ ID 3935, SEQ ID 3936, SEQ ID 3937, SEQ ID 3938, SEQ ID 3939,SEQ ID 3940, SEQ ID 3941, SEQ ID 3942, SEQ ID 3943, SEQ ID 3944, SEQ ID3945, SEQ ID 3946, SEQ ID 3947, and SEQ ID
 3948. 24. The antisenseoligonucleotide progranulin agonist according to claim 22, wherein thecontiguous nucleotide sequence is complementary to a sequence selectedfrom the group consisting of SEQ ID 2321, SEQ ID 2335, SEQ ID 2336, SEQID 2337, SEQ ID 2338, SEQ ID 2339, SEQ ID 2348, SEQ ID 2349, SEQ ID2351, SEQ ID 2352, SEQ ID 2353, SEQ ID 2354, SEQ ID 2355, SEQ ID 2358,SEQ ID 2360, SEQ ID 2364, SEQ ID 2365, SEQ ID 2366, SEQ ID 2367, SEQ ID2369, SEQ ID 2371, SEQ ID 2373, SEQ ID 2375, SEQ ID 2386, SEQ ID 2387,SEQ ID 2388, SEQ ID 2389, SEQ ID 2394, SEQ ID 2403, SEQ ID 2426, SEQ ID2428, SEQ ID 2429, SEQ ID 2430, SEQ ID 2431, SEQ ID 2432, SEQ ID 2435,SEQ ID 2440, SEQ ID 2441, SEQ ID 2442, SEQ ID 2444, SEQ ID 2446, SEQ ID2447, SEQ ID 2450, SEQ ID 2451, SEQ ID 2452, SEQ ID 2453, SEQ ID 2454,SEQ ID 2455, SEQ ID 2456, SEQ ID 2458, SEQ ID 2459, SEQ ID 2461, SEQ ID2463, SEQ ID 2464, SEQ ID 2465, SEQ ID 2466, SEQ ID 2467, SEQ ID 2468,SEQ ID 2469, SEQ ID 2470, SEQ ID 2471, SEQ ID 2472, SEQ ID 2473, SEQ ID2474, SEQ ID 2475, SEQ ID 2476, SEQ ID 2477, SEQ ID 2478, SEQ ID 2482,SEQ ID 2483, SEQ ID 2484, SEQ ID 2485, SEQ ID 2487, SEQ ID 2489, SEQ ID2494, SEQ ID 2495, SEQ ID 2496, SEQ ID 2497, SEQ ID 2499, SEQ ID 2501,SEQ ID 2502, SEQ ID 2504, SEQ ID 2506, SEQ ID 2507, SEQ ID 2508, SEQ ID2509, SEQ ID 2511, SEQ ID 2513, SEQ ID 2515, SEQ ID 2516, SEQ ID 2518,SEQ ID 2519, SEQ ID 2520, SEQ ID 2521, SEQ ID 2523, SEQ ID 2525, SEQ ID2534, SEQ ID 2537, SEQ ID 2544, SEQ ID 2546, SEQ ID 2554, SEQ ID 2555,SEQ ID 2556, SEQ ID 2560, SEQ ID 2561, SEQ ID 2562, SEQ ID 2595, SEQ ID2626, SEQ ID 2628, SEQ ID 2629, SEQ ID 2630, SEQ ID 2631, SEQ ID 2633,SEQ ID 2638, SEQ ID 2639, SEQ ID 2640, SEQ ID 2649, SEQ ID 2651, SEQ ID2652, SEQ ID 2655, SEQ ID 2658, SEQ ID 2665, SEQ ID 2666, SEQ ID 2667,SEQ ID 2669, SEQ ID 2670, SEQ ID 2676, SEQ ID 2677, SEQ ID 2678, SEQ ID2679, SEQ ID 2682, SEQ ID 2686, SEQ ID 2688, SEQ ID 2689, SEQ ID 2691,SEQ ID 2694, SEQ ID 2698, SEQ ID 2699, SEQ ID 2700, SEQ ID 2701, SEQ ID2703, SEQ ID 2706, SEQ ID 2709, SEQ ID 2711, SEQ ID 2712, SEQ ID 2713,SEQ ID 2714, SEQ ID 2719, SEQ ID 2720, SEQ ID 2721, SEQ ID 2737, SEQ ID2739, SEQ ID 2740, SEQ ID 2741, SEQ ID 2742, SEQ ID 2743, SEQ ID 2744,SEQ ID 2745, SEQ ID 2746, SEQ ID 2747, SEQ ID 2748, SEQ ID 2749, SEQ ID2750, SEQ ID 2751, SEQ ID 2752, SEQ ID 2753, SEQ ID 2754, SEQ ID 2755,SEQ ID 2756, SEQ ID 2757, SEQ ID 2758, SEQ ID 2760, SEQ ID 2763, SEQ ID2764, SEQ ID 2765, SEQ ID 2766, SEQ ID 2767, SEQ ID 2768, SEQ ID 2769,SEQ ID 2770, SEQ ID 2771, SEQ ID 2772, SEQ ID 2774, SEQ ID 2816, SEQ ID2817, SEQ ID 2818, SEQ ID 2819, SEQ ID 2820, SEQ ID 2824, SEQ ID 2828,SEQ ID 2829, SEQ ID 2830, SEQ ID 2831, SEQ ID 2832, SEQ ID 2833, SEQ ID2834, SEQ ID 2835, SEQ ID 2836, SEQ ID 2837, SEQ ID 2851, SEQ ID 2852,SEQ ID 2866, SEQ ID 2871, SEQ ID 2872, SEQ ID 2886, SEQ ID 2887, SEQ ID2890, SEQ ID 2891, SEQ ID 2892, SEQ ID 2895, SEQ ID 2896, SEQ ID 2899,SEQ ID 2904, SEQ ID 2910, SEQ ID 2911, SEQ ID 2912, SEQ ID 2913, SEQ ID2914, SEQ ID 2916, SEQ ID 2918, SEQ ID 2919, SEQ ID 2920, SEQ ID 2922,SEQ ID 2925, SEQ ID 2926, SEQ ID 2932, SEQ ID 2939, SEQ ID 2941, SEQ ID2942, SEQ ID 2943, SEQ ID 2972, SEQ ID 2973, SEQ ID 2974, SEQ ID 2975,SEQ ID 2976, SEQ ID 2977, SEQ ID 2980, SEQ ID 2983, SEQ ID 2985, SEQ ID3053, SEQ ID 3054, SEQ ID 3055, SEQ ID 3056, SEQ ID 3058, SEQ ID 3059,SEQ ID 3060, SEQ ID 3061, SEQ ID 3062, SEQ ID 3063, SEQ ID 3064, SEQ ID3065, SEQ ID 3066, SEQ ID 3068, SEQ ID 3069, SEQ ID 3070, SEQ ID 3071,SEQ ID 3072, SEQ ID 3073, SEQ ID 3074, SEQ ID 3075, SEQ ID 3076, SEQ ID3077, SEQ ID 3078, SEQ ID 3079, SEQ ID 3082, SEQ ID 3083, SEQ ID 3084,SEQ ID 3085, SEQ ID 3088, SEQ ID 3089, SEQ ID 3090, SEQ ID 3091, SEQ ID3092, SEQ ID 3095, SEQ ID 3097, SEQ ID 3102, SEQ ID 3106, SEQ ID 3108,SEQ ID 3110, SEQ ID 3116, SEQ ID 3120, SEQ ID 3121, SEQ ID 3125, SEQ ID3126, SEQ ID 3133, SEQ ID 3134, SEQ ID 3135, SEQ ID 3137, SEQ ID 3138,SEQ ID 3140, SEQ ID 3141, SEQ ID 3142, SEQ ID 3143, SEQ ID 3145, SEQ ID3148, SEQ ID 3152, SEQ ID 3153, SEQ ID 3156, SEQ ID 3157, SEQ ID 3158,SEQ ID 3159, SEQ ID 3160, SEQ ID 3161, SEQ ID 3162, SEQ ID 3163, SEQ ID3164, SEQ ID 3165, SEQ ID 3166, SEQ ID 3167, SEQ ID 3168, SEQ ID 3169,SEQ ID 3170, SEQ ID 3172, SEQ ID 3173, SEQ ID 3174, SEQ ID 3175, SEQ ID3176, SEQ ID 3177, SEQ ID 3178, SEQ ID 3179, SEQ ID 3180, SEQ ID 3181,SEQ ID 3182, SEQ ID 3183, SEQ ID 3184, SEQ ID 3186, SEQ ID 3188, SEQ ID3191, SEQ ID 3193, SEQ ID 3196, SEQ ID 3197, SEQ ID 3203, SEQ ID 3205,SEQ ID 3206, SEQ ID 3207, SEQ ID 3210, SEQ ID 3211, SEQ ID 3212, SEQ ID3213, SEQ ID 3214, SEQ ID 3215, SEQ ID 3216, SEQ ID 3217, SEQ ID 3218,SEQ ID 3219, SEQ ID 3221, SEQ ID 3222, SEQ ID 3223, SEQ ID 3224, SEQ ID3227, SEQ ID 3236, SEQ ID 3237, SEQ ID 3238, SEQ ID 3239, SEQ ID 3240,SEQ ID 3241, SEQ ID 3242, SEQ ID 3243, SEQ ID 3244, SEQ ID 3245, SEQ ID3246, SEQ ID 3248, SEQ ID 3249, SEQ ID 3250, SEQ ID 3251, SEQ ID 3252,SEQ ID 3254, SEQ ID 3258, SEQ ID 3259, SEQ ID 3261, SEQ ID 3263, SEQ ID3265, SEQ ID 3266, SEQ ID 3267, SEQ ID 3271, SEQ ID 3272, SEQ ID 3273,SEQ ID 3276, SEQ ID 3277, SEQ ID 3279, SEQ ID 3286, SEQ ID 3295, SEQ ID3297, SEQ ID 3305, SEQ ID 3307, SEQ ID 3309, SEQ ID 3312, SEQ ID 3313,SEQ ID 3314, SEQ ID 3316, SEQ ID 3317, SEQ ID 3318, SEQ ID 3320, SEQ ID3332, SEQ ID 3335, SEQ ID 3336, SEQ ID 3337, SEQ ID 3338, SEQ ID 3339,SEQ ID 3340, SEQ ID 3342, SEQ ID 3343, SEQ ID 3345, SEQ ID 3346, SEQ ID3347, SEQ ID 3348, SEQ ID 3349, SEQ ID 3350, SEQ ID 3351, SEQ ID 3352,SEQ ID 3353, SEQ ID 3354, SEQ ID 3355, SEQ ID 3356, SEQ ID 3359, SEQ ID3360, SEQ ID 3361, SEQ ID 3362, SEQ ID 3363, SEQ ID 3364, SEQ ID 3365,SEQ ID 3366, SEQ ID 3369, SEQ ID 3370, SEQ ID 3390, SEQ ID 3392, SEQ ID3393, SEQ ID 3394, SEQ ID 3395, SEQ ID 3396, SEQ ID 3397, SEQ ID 3398,SEQ ID 3399, SEQ ID 3401, SEQ ID 3403, SEQ ID 3404, SEQ ID 3407, SEQ ID3408, SEQ ID 3409, SEQ ID 3410, SEQ ID 3411, SEQ ID 3412, SEQ ID 3413,SEQ ID 3414, SEQ ID 3415, SEQ ID 3417, SEQ ID 3419, SEQ ID 3420, SEQ ID3422, SEQ ID 3423, SEQ ID 3424, SEQ ID 3428, SEQ ID 3429, SEQ ID 3430,SEQ ID 3432, SEQ ID 3433, SEQ ID 3434, SEQ ID 3435, SEQ ID 3436, SEQ ID3437, SEQ ID 3439, SEQ ID 3440, SEQ ID 3441, SEQ ID 3442, SEQ ID 3443,SEQ ID 3444, SEQ ID 3445, SEQ ID 3446, SEQ ID 3447, SEQ ID 3448, SEQ ID3449, SEQ ID 3450, SEQ ID 3451, SEQ ID 3452, SEQ ID 3460, SEQ ID 3461,SEQ ID 3466, SEQ ID 3467, SEQ ID 3468, SEQ ID 3490, SEQ ID 3494, SEQ ID3496, SEQ ID 3501, SEQ ID 3505, SEQ ID 3511, SEQ ID 3512, SEQ ID 3516,SEQ ID 3517, SEQ ID 3521, SEQ ID 3522, SEQ ID 3556, SEQ ID 3557, SEQ ID3561, SEQ ID 3566, SEQ ID 3567, SEQ ID 3568, SEQ ID 3569, SEQ ID 3571,SEQ ID 3572, SEQ ID 3576, SEQ ID 3578, SEQ ID 3580, SEQ ID 3584, SEQ ID3594, SEQ ID 3613, SEQ ID 3614, SEQ ID 3624, SEQ ID 3625, SEQ ID 3626,SEQ ID 3627, SEQ ID 3628, SEQ ID 3633, SEQ ID 3641, SEQ ID 3643, SEQ ID3648, SEQ ID 3651, SEQ ID 3654, SEQ ID 3656, SEQ ID 3659, SEQ ID 3660,SEQ ID 3661, SEQ ID 3670, SEQ ID 3676, SEQ ID 3680, SEQ ID 3681, SEQ ID3683, SEQ ID 3684, SEQ ID 3685, SEQ ID 3686, SEQ ID 3687, SEQ ID 3688,SEQ ID 3689, SEQ ID 3691, SEQ ID 3693, SEQ ID 3694, SEQ ID 3695, SEQ ID3696, SEQ ID 3698, SEQ ID 3700, SEQ ID 3701, SEQ ID 3703, SEQ ID 3704,SEQ ID 3707, SEQ ID 3708, SEQ ID 3709, SEQ ID 3710, SEQ ID 3711, SEQ ID3712, SEQ ID 3713, SEQ ID 3714, SEQ ID 3715, SEQ ID 3716, SEQ ID 3717,SEQ ID 3718, SEQ ID 3719, SEQ ID 3720, SEQ ID 3721, SEQ ID 3722, SEQ ID3723, SEQ ID 3725, SEQ ID 3744, SEQ ID 3747, SEQ ID 3748, SEQ ID 3749,SEQ ID 3750, SEQ ID 3751, SEQ ID 3752, SEQ ID 3753, SEQ ID 3754, SEQ ID3755, SEQ ID 3774, SEQ ID 3775, SEQ ID 3776, SEQ ID 3786, SEQ ID 3788,SEQ ID 3790, SEQ ID 3791, SEQ ID 3793, SEQ ID 3794, SEQ ID 3795, SEQ ID3796, SEQ ID 3797, SEQ ID 3798, SEQ ID 3799, SEQ ID 3800, SEQ ID 3801,SEQ ID 3802, SEQ ID 3803, SEQ ID 3804, SEQ ID 3805, SEQ ID 3809, SEQ ID3810, SEQ ID 3811, SEQ ID 3812, SEQ ID 3813, SEQ ID 3814, SEQ ID 3815,SEQ ID 3821, SEQ ID 3822, SEQ ID 3823, SEQ ID 3824, SEQ ID 3825, SEQ ID3826, SEQ ID 3827, SEQ ID 3828, SEQ ID 3830, SEQ ID 3831, SEQ ID 3832,SEQ ID 3834, SEQ ID 3836, SEQ ID 3837, SEQ ID 3838, SEQ ID 3839, SEQ ID3840, SEQ ID 3841, SEQ ID 3842, SEQ ID 3844, SEQ ID 3850, SEQ ID 3852,SEQ ID 3867, SEQ ID 3868, SEQ ID 3870, SEQ ID 3871, SEQ ID 3872, SEQ ID3873, SEQ ID 3874, SEQ ID 3875, SEQ ID 3876, SEQ ID 3879, SEQ ID 3880,SEQ ID 3881, SEQ ID 3882, SEQ ID 3883, SEQ ID 3884, SEQ ID 3885, SEQ ID3886, SEQ ID 3887, SEQ ID 3888, SEQ ID 3889, SEQ ID 3890, SEQ ID 3891,SEQ ID 3892, SEQ ID 3893, SEQ ID 3894, SEQ ID 3895, SEQ ID 3896, SEQ ID3897, SEQ ID 3908, SEQ ID 3909, SEQ ID 3910, SEQ ID 3911, SEQ ID 3912,SEQ ID 3913, SEQ ID 3922, SEQ ID 3923, SEQ ID 3930, SEQ ID 3935, SEQ ID3936, SEQ ID 3937, SEQ ID 3938, SEQ ID 3939, SEQ ID 3940, SEQ ID 3944,SEQ ID 3945, SEQ ID 3946, SEQ ID 3947, and SEQ ID
 3948. 25. Theantisense oligonucleotide progranulin agonist according to any one ofclaims 22-24, wherein the antisense oligonucleotide progranulin agonistis selected from the group consisting of SEQ ID NOs 693-2039.
 26. Theantisense oligonucleotide progranulin agonist according to any one ofclaims 22-25, wherein the antisense oligonucleotide progranulin agonistis selected from the group consisting of SEQ ID 693, SEQ ID 694, SEQ ID696, SEQ ID 700, SEQ ID 701, SEQ ID 703, SEQ ID 706, SEQ ID 707, SEQ ID708, SEQ ID 709, SEQ ID 710, SEQ ID 711, SEQ ID 712, SEQ ID 713, SEQ ID714, SEQ ID 717, SEQ ID 718, SEQ ID 719, SEQ ID 720, SEQ ID 721, SEQ ID722, SEQ ID 723, SEQ ID 724, SEQ ID 725, SEQ ID 726, SEQ ID 727, SEQ ID728, SEQ ID 729, SEQ ID 730, SEQ ID 731, SEQ ID 732, SEQ ID 733, SEQ ID734, SEQ ID 736, SEQ ID 737, SEQ ID 738, SEQ ID 739, SEQ ID 740, SEQ ID741, SEQ ID 742, SEQ ID 743, SEQ ID 744, SEQ ID 745, SEQ ID 746, SEQ ID747, SEQ ID 748, SEQ ID 749, SEQ ID 750, SEQ ID 751, SEQ ID 752, SEQ ID753, SEQ ID 756, SEQ ID 758, SEQ ID 759, SEQ ID 760, SEQ ID 761, SEQ ID762, SEQ ID 764, SEQ ID 765, SEQ ID 766, SEQ ID 767, SEQ ID 768, SEQ ID769, SEQ ID 770, SEQ ID 771, SEQ ID 772, SEQ ID 773, SEQ ID 775, SEQ ID776, SEQ ID 777, SEQ ID 778, SEQ ID 779, SEQ ID 780, SEQ ID 782, SEQ ID783, SEQ ID 785, SEQ ID 786, SEQ ID 787, SEQ ID 788, SEQ ID 790, SEQ ID791, SEQ ID 793, SEQ ID 796, SEQ ID 797, SEQ ID 798, SEQ ID 799, SEQ ID800, SEQ ID 801, SEQ ID 802, SEQ ID 803, SEQ ID 804, SEQ ID 805, SEQ ID806, SEQ ID 807, SEQ ID 808, SEQ ID 809, SEQ ID 810, SEQ ID 811, SEQ ID812, SEQ ID 813, SEQ ID 814, SEQ ID 815, SEQ ID 816, SEQ ID 817, SEQ ID818, SEQ ID 819, SEQ ID 820, SEQ ID 821, SEQ ID 822, SEQ ID 823, SEQ ID824, SEQ ID 825, SEQ ID 826, SEQ ID 827, SEQ ID 828, SEQ ID 829, SEQ ID830, SEQ ID 831, SEQ ID 832, SEQ ID 833, SEQ ID 834, SEQ ID 835, SEQ ID836, SEQ ID 837, SEQ ID 838, SEQ ID 839, SEQ ID 840, SEQ ID 841, SEQ ID842, SEQ ID 843, SEQ ID 844, SEQ ID 845, SEQ ID 846, SEQ ID 847, SEQ ID848, SEQ ID 849, SEQ ID 850, SEQ ID 851, SEQ ID 853, SEQ ID 854, SEQ ID855, SEQ ID 856, SEQ ID 857, SEQ ID 859, SEQ ID 861, SEQ ID 862, SEQ ID863, SEQ ID 864, SEQ ID 865, SEQ ID 866, SEQ ID 867, SEQ ID 868, SEQ ID869, SEQ ID 870, SEQ ID 871, SEQ ID 873, SEQ ID 874, SEQ ID 875, SEQ ID876, SEQ ID 877, SEQ ID 878, SEQ ID 879, SEQ ID 880, SEQ ID 881, SEQ ID882, SEQ ID 883, SEQ ID 884, SEQ ID 885, SEQ ID 886, SEQ ID 887, SEQ ID888, SEQ ID 890, SEQ ID 891, SEQ ID 892, SEQ ID 893, SEQ ID 894, SEQ ID895, SEQ ID 896, SEQ ID 897, SEQ ID 898, SEQ ID 899, SEQ ID 900, SEQ ID903, SEQ ID 905, SEQ ID 906, SEQ ID 907, SEQ ID 908, SEQ ID 909, SEQ ID910, SEQ ID 912, SEQ ID 913, SEQ ID 914, SEQ ID 916, SEQ ID 918, SEQ ID919, SEQ ID 921, SEQ ID 922, SEQ ID 923, SEQ ID 925, SEQ ID 926, SEQ ID927, SEQ ID 928, SEQ ID 929, SEQ ID 932, SEQ ID 933, SEQ ID 934, SEQ ID935, SEQ ID 937, SEQ ID 938, SEQ ID 939, SEQ ID 944, SEQ ID 945, SEQ ID946, SEQ ID 947, SEQ ID 948, SEQ ID 949, SEQ ID 950, SEQ ID 951, SEQ ID952, SEQ ID 953, SEQ ID 954, SEQ ID 955, SEQ ID 956, SEQ ID 957, SEQ ID958, SEQ ID 960, SEQ ID 961, SEQ ID 962, SEQ ID 963, SEQ ID 964, SEQ ID965, SEQ ID 966, SEQ ID 967, SEQ ID 968, SEQ ID 969, SEQ ID 970, SEQ ID971, SEQ ID 973, SEQ ID 974, SEQ ID 975, SEQ ID 976, SEQ ID 978, SEQ ID982, SEQ ID 985, SEQ ID 986, SEQ ID 987, SEQ ID 991, SEQ ID 994, SEQ ID995, SEQ ID 996, SEQ ID 997, SEQ ID 998, SEQ ID 999, SEQ ID 1000, SEQ ID1001, SEQ ID 1002, SEQ ID 1003, SEQ ID 1004, SEQ ID 1005, SEQ ID 1006,SEQ ID 1007, SEQ ID 1008, SEQ ID 1009, SEQ ID 1010, SEQ ID 1011, SEQ ID1012, SEQ ID 1013, SEQ ID 1014, SEQ ID 1015, SEQ ID 1016, SEQ ID 1017,SEQ ID 1018, SEQ ID 1019, SEQ ID 1020, SEQ ID 1021, SEQ ID 1022, SEQ ID1023, SEQ ID 1024, SEQ ID 1025, SEQ ID 1026, SEQ ID 1027, SEQ ID 1028,SEQ ID 1030, SEQ ID 1031, SEQ ID 1032, SEQ ID 1033, SEQ ID 1034, SEQ ID1035, SEQ ID 1036, SEQ ID 1037, SEQ ID 1038, SEQ ID 1039, SEQ ID 1040,SEQ ID 1041, SEQ ID 1042, SEQ ID 1043, SEQ ID 1044, SEQ ID 1045, SEQ ID1046, SEQ ID 1047, SEQ ID 1048, SEQ ID 1049, SEQ ID 1050, SEQ ID 1051,SEQ ID 1052, SEQ ID 1053, SEQ ID 1054, SEQ ID 1055, SEQ ID 1056, SEQ ID1057, SEQ ID 1058, SEQ ID 1059, SEQ ID 1060, SEQ ID 1061, SEQ ID 1062,SEQ ID 1063, SEQ ID 1065, SEQ ID 1066, SEQ ID 1067, SEQ ID 1068, SEQ ID1069, SEQ ID 1070, SEQ ID 1071, SEQ ID 1072, SEQ ID 1073, SEQ ID 1074,SEQ ID 1075, SEQ ID 1076, SEQ ID 1077, SEQ ID 1078, SEQ ID 1079, SEQ ID1080, SEQ ID 1081, SEQ ID 1082, SEQ ID 1083, SEQ ID 1084, SEQ ID 1085,SEQ ID 1086, SEQ ID 1087, SEQ ID 1088, SEQ ID 1089, SEQ ID 1090, SEQ ID1091, SEQ ID 1092, SEQ ID 1093, SEQ ID 1094, SEQ ID 1095, SEQ ID 1098,SEQ ID 1099, SEQ ID 1100, SEQ ID 1101, SEQ ID 1102, SEQ ID 1105, SEQ ID1106, SEQ ID 1107, SEQ ID 1108, SEQ ID 1109, SEQ ID 1110, SEQ ID 1111,SEQ ID 1112, SEQ ID 1113, SEQ ID 1114, SEQ ID 1115, SEQ ID 1116, SEQ ID1117, SEQ ID 1118, SEQ ID 1119, SEQ ID 1120, SEQ ID 1121, SEQ ID 1122,SEQ ID 1123, SEQ ID 1124, SEQ ID 1125, SEQ ID 1126, SEQ ID 1127, SEQ ID1128, SEQ ID 1129, SEQ ID 1130, SEQ ID 1131, SEQ ID 1132, SEQ ID 1133,SEQ ID 1134, SEQ ID 1135, SEQ ID 1136, SEQ ID 1137, SEQ ID 1138, SEQ ID1139, SEQ ID 1140, SEQ ID 1141, SEQ ID 1142, SEQ ID 1143, SEQ ID 1144,SEQ ID 1145, SEQ ID 1146, SEQ ID 1147, SEQ ID 1187, SEQ ID 1188, SEQ ID1189, SEQ ID 1190, SEQ ID 1191, SEQ ID 1192, SEQ ID 1193, SEQ ID 1194,SEQ ID 1195, SEQ ID 1196, SEQ ID 1197, SEQ ID 1198, SEQ ID 1199, SEQ ID1200, SEQ ID 1201, SEQ ID 1202, SEQ ID 1203, SEQ ID 1204, SEQ ID 1205,SEQ ID 1206, SEQ ID 1207, SEQ ID 1208, SEQ ID 1209, SEQ ID 1210, SEQ ID1211, SEQ ID 1212, SEQ ID 1213, SEQ ID 1214, SEQ ID 1215, SEQ ID 1216,SEQ ID 1217, SEQ ID 1219, SEQ ID 1220, SEQ ID 1221, SEQ ID 1222, SEQ ID1223, SEQ ID 1224, SEQ ID 1225, SEQ ID 1226, SEQ ID 1227, SEQ ID 1230,SEQ ID 1231, SEQ ID 1232, SEQ ID 1233, SEQ ID 1234, SEQ ID 1235, SEQ ID1236, SEQ ID 1237, SEQ ID 1238, SEQ ID 1239, SEQ ID 1240, SEQ ID 1241,SEQ ID 1242, SEQ ID 1243, SEQ ID 1244, SEQ ID 1245, SEQ ID 1246, SEQ ID1247, SEQ ID 1248, SEQ ID 1250, SEQ ID 1251, SEQ ID 1252, SEQ ID 1253,SEQ ID 1254, SEQ ID 1255, SEQ ID 1256, SEQ ID 1257, SEQ ID 1258, SEQ ID1259, SEQ ID 1260, SEQ ID 1261, SEQ ID 1262, SEQ ID 1263, SEQ ID 1264,SEQ ID 1265, SEQ ID 1266, SEQ ID 1267, SEQ ID 1268, SEQ ID 1269, SEQ ID1270, SEQ ID 1271, SEQ ID 1272, SEQ ID 1273, SEQ ID 1274, SEQ ID 1275,SEQ ID 1276, SEQ ID 1277, SEQ ID 1278, SEQ ID 1279, SEQ ID 1280, SEQ ID1281, SEQ ID 1282, SEQ ID 1283, SEQ ID 1284, SEQ ID 1285, SEQ ID 1286,SEQ ID 1287, SEQ ID 1288, SEQ ID 1289, SEQ ID 1290, SEQ ID 1291, SEQ ID1292, SEQ ID 1293, SEQ ID 1294, SEQ ID 1295, SEQ ID 1296, SEQ ID 1297,SEQ ID 1298, SEQ ID 1299, SEQ ID 1300, SEQ ID 1301, SEQ ID 1302, SEQ ID1303, SEQ ID 1304, SEQ ID 1306, SEQ ID 1307, SEQ ID 1308, SEQ ID 1309,SEQ ID 1310, SEQ ID 1311, SEQ ID 1312, SEQ ID 1313, SEQ ID 1314, SEQ ID1315, SEQ ID 1316, SEQ ID 1317, SEQ ID 1318, SEQ ID 1319, SEQ ID 1320,SEQ ID 1321, SEQ ID 1322, SEQ ID 1323, SEQ ID 1325, SEQ ID 1326, SEQ ID1327, SEQ ID 1328, SEQ ID 1329, SEQ ID 1330, SEQ ID 1332, SEQ ID 1333,SEQ ID 1335, SEQ ID 1336, SEQ ID 1337, SEQ ID 1338, SEQ ID 1339, SEQ ID1341, SEQ ID 1342, SEQ ID 1343, SEQ ID 1344, SEQ ID 1345, SEQ ID 1346,SEQ ID 1347, SEQ ID 1348, SEQ ID 1349, SEQ ID 1350, SEQ ID 1351, SEQ ID1352, SEQ ID 1353, SEQ ID 1354, SEQ ID 1355, SEQ ID 1356, SEQ ID 1357,SEQ ID 1425, SEQ ID 1426, SEQ ID 1427, SEQ ID 1428, SEQ ID 1429, SEQ ID1430, SEQ ID 1431, SEQ ID 1432, SEQ ID 1433, SEQ ID 1434, SEQ ID 1435,SEQ ID 1436, SEQ ID 1437, SEQ ID 1438, SEQ ID 1440, SEQ ID 1441, SEQ ID1442, SEQ ID 1443, SEQ ID 1444, SEQ ID 1445, SEQ ID 1446, SEQ ID 1447,SEQ ID 1448, SEQ ID 1449, SEQ ID 1450, SEQ ID 1451, SEQ ID 1452, SEQ ID1453, SEQ ID 1454, SEQ ID 1455, SEQ ID 1456, SEQ ID 1457, SEQ ID 1458,SEQ ID 1459, SEQ ID 1460, SEQ ID 1461, SEQ ID 1462, SEQ ID 1463, SEQ ID1464, SEQ ID 1465, SEQ ID 1466, SEQ ID 1467, SEQ ID 1469, SEQ ID 1470,SEQ ID 1471, SEQ ID 1472, SEQ ID 1474, SEQ ID 1475, SEQ ID 1476, SEQ ID1477, SEQ ID 1478, SEQ ID 1479, SEQ ID 1480, SEQ ID 1481, SEQ ID 1482,SEQ ID 1484, SEQ ID 1485, SEQ ID 1487, SEQ ID 1488, SEQ ID 1489, SEQ ID1491, SEQ ID 1492, SEQ ID 1493, SEQ ID 1494, SEQ ID 1495, SEQ ID 1496,SEQ ID 1497, SEQ ID 1498, SEQ ID 1499, SEQ ID 1500, SEQ ID 1501, SEQ ID1502, SEQ ID 1503, SEQ ID 1504, SEQ ID 1505, SEQ ID 1506, SEQ ID 1507,SEQ ID 1508, SEQ ID 1509, SEQ ID 1510, SEQ ID 1511, SEQ ID 1512, SEQ ID1513, SEQ ID 1514, SEQ ID 1515, SEQ ID 1516, SEQ ID 1517, SEQ ID 1518,SEQ ID 1519, SEQ ID 1520, SEQ ID 1521, SEQ ID 1522, SEQ ID 1523, SEQ ID1524, SEQ ID 1525, SEQ ID 1526, SEQ ID 1527, SEQ ID 1528, SEQ ID 1529,SEQ ID 1530, SEQ ID 1531, SEQ ID 1532, SEQ ID 1533, SEQ ID 1534, SEQ ID1535, SEQ ID 1536, SEQ ID 1537, SEQ ID 1538, SEQ ID 1539, SEQ ID 1540,SEQ ID 1541, SEQ ID 1542, SEQ ID 1543, SEQ ID 1544, SEQ ID 1545, SEQ ID1546, SEQ ID 1547, SEQ ID 1548, SEQ ID 1549, SEQ ID 1550, SEQ ID 1551,SEQ ID 1552, SEQ ID 1553, SEQ ID 1554, SEQ ID 1555, SEQ ID 1556, SEQ ID1557, SEQ ID 1558, SEQ ID 1559, SEQ ID 1560, SEQ ID 1561, SEQ ID 1562,SEQ ID 1563, SEQ ID 1564, SEQ ID 1565, SEQ ID 1566, SEQ ID 1567, SEQ ID1568, SEQ ID 1569, SEQ ID 1570, SEQ ID 1571, SEQ ID 1572, SEQ ID 1573,SEQ ID 1574, SEQ ID 1575, SEQ ID 1576, SEQ ID 1577, SEQ ID 1578, SEQ ID1579, SEQ ID 1580, SEQ ID 1581, SEQ ID 1582, SEQ ID 1583, SEQ ID 1584,SEQ ID 1585, SEQ ID 1586, SEQ ID 1587, SEQ ID 1588, SEQ ID 1589, SEQ ID1590, SEQ ID 1591, SEQ ID 1592, SEQ ID 1593, SEQ ID 1594, SEQ ID 1595,SEQ ID 1596, SEQ ID 1597, SEQ ID 1598, SEQ ID 1599, SEQ ID 1600, SEQ ID1601, SEQ ID 1602, SEQ ID 1603, SEQ ID 1604, SEQ ID 1605, SEQ ID 1606,SEQ ID 1607, SEQ ID 1608, SEQ ID 1609, SEQ ID 1610, SEQ ID 1611, SEQ ID1612, SEQ ID 1613, SEQ ID 1614, SEQ ID 1615, SEQ ID 1616, SEQ ID 1617,SEQ ID 1618, SEQ ID 1620, SEQ ID 1621, SEQ ID 1622, SEQ ID 1623, SEQ ID1624, SEQ ID 1625, SEQ ID 1626, SEQ ID 1627, SEQ ID 1628, SEQ ID 1629,SEQ ID 1630, SEQ ID 1631, SEQ ID 1632, SEQ ID 1633, SEQ ID 1634, SEQ ID1635, SEQ ID 1636, SEQ ID 1637, SEQ ID 1638, SEQ ID 1639, SEQ ID 1640,SEQ ID 1641, SEQ ID 1642, SEQ ID 1643, SEQ ID 1644, SEQ ID 1645, SEQ ID1647, SEQ ID 1648, SEQ ID 1649, SEQ ID 1650, SEQ ID 1651, SEQ ID 1652,SEQ ID 1654, SEQ ID 1656, SEQ ID 1657, SEQ ID 1658, SEQ ID 1659, SEQ ID1660, SEQ ID 1661, SEQ ID 1663, SEQ ID 1664, SEQ ID 1665, SEQ ID 1666,SEQ ID 1667, SEQ ID 1668, SEQ ID 1669, SEQ ID 1670, SEQ ID 1671, SEQ ID1672, SEQ ID 1673, SEQ ID 1674, SEQ ID 1675, SEQ ID 1676, SEQ ID 1677,SEQ ID 1678, SEQ ID 1679, SEQ ID 1680, SEQ ID 1681, SEQ ID 1682, SEQ ID1683, SEQ ID 1684, SEQ ID 1685, SEQ ID 1686, SEQ ID 1687, SEQ ID 1688,SEQ ID 1689, SEQ ID 1690, SEQ ID 1692, SEQ ID 1693, SEQ ID 1694, SEQ ID1695, SEQ ID 1696, SEQ ID 1697, SEQ ID 1698, SEQ ID 1699, SEQ ID 1701,SEQ ID 1703, SEQ ID 1704, SEQ ID 1705, SEQ ID 1706, SEQ ID 1707, SEQ ID1708, SEQ ID 1709, SEQ ID 1710, SEQ ID 1711, SEQ ID 1712, SEQ ID 1714,SEQ ID 1715, SEQ ID 1716, SEQ ID 1717, SEQ ID 1718, SEQ ID 1719, SEQ ID1720, SEQ ID 1721, SEQ ID 1722, SEQ ID 1723, SEQ ID 1724, SEQ ID 1725,SEQ ID 1726, SEQ ID 1727, SEQ ID 1728, SEQ ID 1729, SEQ ID 1730, SEQ ID1731, SEQ ID 1732, SEQ ID 1733, SEQ ID 1734, SEQ ID 1735, SEQ ID 1736,SEQ ID 1737, SEQ ID 1738, SEQ ID 1739, SEQ ID 1740, SEQ ID 1741, SEQ ID1742, SEQ ID 1743, SEQ ID 1762, SEQ ID 1763, SEQ ID 1764, SEQ ID 1765,SEQ ID 1766, SEQ ID 1767, SEQ ID 1768, SEQ ID 1769, SEQ ID 1770, SEQ ID1771, SEQ ID 1772, SEQ ID 1773, SEQ ID 1774, SEQ ID 1775, SEQ ID 1776,SEQ ID 1777, SEQ ID 1778, SEQ ID 1779, SEQ ID 1780, SEQ ID 1781, SEQ ID1782, SEQ ID 1783, SEQ ID 1784, SEQ ID 1785, SEQ ID 1786, SEQ ID 1787,SEQ ID 1788, SEQ ID 1789, SEQ ID 1790, SEQ ID 1791, SEQ ID 1792, SEQ ID1793, SEQ ID 1794, SEQ ID 1795, SEQ ID 1796, SEQ ID 1797, SEQ ID 1798,SEQ ID 1799, SEQ ID 1800, SEQ ID 1801, SEQ ID 1802, SEQ ID 1803, SEQ ID1804, SEQ ID 1805, SEQ ID 1806, SEQ ID 1807, SEQ ID 1808, SEQ ID 1809,SEQ ID 1810, SEQ ID 1811, SEQ ID 1812, SEQ ID 1813, SEQ ID 1814, SEQ ID1815, SEQ ID 1816, SEQ ID 1817, SEQ ID 1818, SEQ ID 1819, SEQ ID 1820,SEQ ID 1821, SEQ ID 1822, SEQ ID 1823, SEQ ID 1824, SEQ ID 1825, SEQ ID1826, SEQ ID 1832, SEQ ID 1833, SEQ ID 1836, SEQ ID 1837, SEQ ID 1838,SEQ ID 1839, SEQ ID 1840, SEQ ID 1858, SEQ ID 1859, SEQ ID 1860, SEQ ID1861, SEQ ID 1862, SEQ ID 1863, SEQ ID 1865, SEQ ID 1866, SEQ ID 1868,SEQ ID 1869, SEQ ID 1873, SEQ ID 1877, SEQ ID 1880, SEQ ID 1883, SEQ ID1884, SEQ ID 1888, SEQ ID 1889, SEQ ID 1890, SEQ ID 1893, SEQ ID 1894,SEQ ID 1895, SEQ ID 1896, SEQ ID 1897, SEQ ID 1898, SEQ ID 1899, SEQ ID1900, SEQ ID 1902, SEQ ID 1903, SEQ ID 1904, SEQ ID 1906, SEQ ID 1907,SEQ ID 1908, SEQ ID 1910, SEQ ID 1911, SEQ ID 1913, SEQ ID 1914, SEQ ID1915, SEQ ID 1916, SEQ ID 1918, SEQ ID 1920, SEQ ID 1921, SEQ ID 1922,SEQ ID 1924, SEQ ID 1928, SEQ ID 1929, SEQ ID 1930, SEQ ID 1932, SEQ ID1933, SEQ ID 1938, SEQ ID 1939, SEQ ID 1940, SEQ ID 1941, SEQ ID 1943,SEQ ID 1944, SEQ ID 1945, SEQ ID 1946, SEQ ID 1948, SEQ ID 1949, SEQ ID1950, SEQ ID 1952, SEQ ID 1953, SEQ ID 1956, SEQ ID 1957, SEQ ID 1958,SEQ ID 1960, SEQ ID 1962, SEQ ID 1964, SEQ ID 1966, SEQ ID 1967, SEQ ID1970, SEQ ID 1971, SEQ ID 1972, SEQ ID 1973, SEQ ID 1974, SEQ ID 1975,SEQ ID 1977, SEQ ID 1979, SEQ ID 1981, SEQ ID 1982, SEQ ID 1985, SEQ ID1986, SEQ ID 1987, SEQ ID 1988, SEQ ID 1989, SEQ ID 1993, SEQ ID 1995,SEQ ID 1996, SEQ ID 1997, SEQ ID 1998, SEQ ID 1999, SEQ ID 2000, SEQ ID2001, SEQ ID 2002, SEQ ID 2003, SEQ ID 2004, SEQ ID 2005, SEQ ID 2008,SEQ ID 2009, SEQ ID 2010, SEQ ID 2011, SEQ ID 2013, SEQ ID 2014, SEQ ID2015, SEQ ID 2017, SEQ ID 2019, SEQ ID 2020, SEQ ID 2021, SEQ ID 2023,SEQ ID 2026, SEQ ID 2028, SEQ ID 2031, SEQ ID 2032, SEQ ID 2033, SEQ ID2035, SEQ ID 2036, SEQ ID 2037, SEQ ID 2038, SEQ ID 2042, SEQ ID 2044,SEQ ID 2048, SEQ ID 2050, SEQ ID 2051, SEQ ID 2052, SEQ ID 2053, SEQ ID2054, SEQ ID 2055, SEQ ID 2056, SEQ ID 2057, SEQ ID 2058, SEQ ID 2059,SEQ ID 2060, SEQ ID 2061, SEQ ID 2062, SEQ ID 2063, SEQ ID 2064, SEQ ID2065, SEQ ID 2066, SEQ ID 2067, SEQ ID 2068, SEQ ID 2069, SEQ ID 2070,SEQ ID 2071, SEQ ID 2072, SEQ ID 2073, SEQ ID 2074, SEQ ID 2075, SEQ ID2076, SEQ ID 2077, SEQ ID 2078, SEQ ID 2079, SEQ ID 2080, SEQ ID 2081,SEQ ID 2082, SEQ ID 2083, SEQ ID 2084, SEQ ID 2085, SEQ ID 2086, SEQ ID2087, SEQ ID 2088, SEQ ID 2089, SEQ ID 2090, SEQ ID 2091, SEQ ID 2092,SEQ ID 2093, SEQ ID 2094, SEQ ID 2095, SEQ ID 2096, SEQ ID 2097, SEQ ID2098, SEQ ID 2099, SEQ ID 2101, SEQ ID 2102, SEQ ID 2103, SEQ ID 2104,SEQ ID 2105, SEQ ID 2106, SEQ ID 2107, SEQ ID 2108, SEQ ID 2109, SEQ ID2110, SEQ ID 2111, SEQ ID 2112, SEQ ID 2113, SEQ ID 2114, SEQ ID 2115,SEQ ID 2116, SEQ ID 2117, SEQ ID 2118, SEQ ID 2119, SEQ ID 2120, SEQ ID2121, SEQ ID 2122, SEQ ID 2123, SEQ ID 2124, SEQ ID 2125, SEQ ID 2126,SEQ ID 2127, SEQ ID 2146, SEQ ID 2147, SEQ ID 2148, SEQ ID 2149, SEQ ID2150, SEQ ID 2151, SEQ ID 2152, SEQ ID 2153, SEQ ID 2154, SEQ ID 2155,SEQ ID 2156, SEQ ID 2157, SEQ ID 2158, SEQ ID 2159, SEQ ID 2160, SEQ ID2161, SEQ ID 2162, SEQ ID 2163, SEQ ID 2164, SEQ ID 2165, SEQ ID 2166,SEQ ID 2167, SEQ ID 2168, SEQ ID 2169, SEQ ID 2170, SEQ ID 2171, SEQ ID2172, SEQ ID 2173, SEQ ID 2174, SEQ ID 2175, SEQ ID 2176, SEQ ID 2177,SEQ ID 2178, SEQ ID 2179, SEQ ID 2180, SEQ ID 2181, SEQ ID 2182, SEQ ID2183, SEQ ID 2184, SEQ ID 2185, SEQ ID 2186, SEQ ID 2187, SEQ ID 2188,SEQ ID 2189, SEQ ID 2190, SEQ ID 2191, SEQ ID 2192, SEQ ID 2193, SEQ ID2194, SEQ ID 2195, SEQ ID 2196, SEQ ID 2197, SEQ ID 2198, SEQ ID 2199,SEQ ID 2200, SEQ ID 2201, SEQ ID 2202, SEQ ID 2203, SEQ ID 2204, SEQ ID2205, SEQ ID 2206, SEQ ID 2207, SEQ ID 2208, SEQ ID 2209, SEQ ID 2210,SEQ ID 2211, SEQ ID 2212, SEQ ID 2213, SEQ ID 2214, SEQ ID 2216, SEQ ID2220, SEQ ID 2222, SEQ ID 2223, SEQ ID 2224, SEQ ID 2225, SEQ ID 2239,SEQ ID 2240, SEQ ID 2241, SEQ ID 2242, SEQ ID 2243, SEQ ID 2244, SEQ ID2245, SEQ ID 2246, SEQ ID 2247, SEQ ID 2248, SEQ ID 2249, SEQ ID 2250,SEQ ID 2251, SEQ ID 2252, SEQ ID 2253, SEQ ID 2254, SEQ ID 2255, SEQ ID2256, SEQ ID 2257, SEQ ID 2258, SEQ ID 2259, SEQ ID 2260, SEQ ID 2261,SEQ ID 2262, SEQ ID 2263, SEQ ID 2264, SEQ ID 2265, SEQ ID 2266, SEQ ID2267, SEQ ID 2268, SEQ ID 2269, SEQ ID 2270, SEQ ID 2271, SEQ ID 2272,SEQ ID 2273, SEQ ID 2274, SEQ ID 2275, SEQ ID 2276, SEQ ID 2277, SEQ ID2278, SEQ ID 2279, SEQ ID 2280, SEQ ID 2281, SEQ ID 2282, SEQ ID 2283,SEQ ID 2284, SEQ ID 2285, SEQ ID 2286, SEQ ID 2287, SEQ ID 2288, SEQ ID2289, SEQ ID 2290, SEQ ID 2291, SEQ ID 2292, SEQ ID 2293, SEQ ID 2294,SEQ ID 2295, SEQ ID 2296, SEQ ID 2297, SEQ ID 2298, SEQ ID 2299, SEQ ID2300, SEQ ID 2301, SEQ ID 2302, SEQ ID 2303, SEQ ID 2304, SEQ ID 2305,SEQ ID 2306, SEQ ID 2307, SEQ ID 2308, SEQ ID 2309, SEQ ID 2310, SEQ ID2311, SEQ ID 2312, SEQ ID 2313, SEQ ID 2314, SEQ ID 2315, SEQ ID 2316,SEQ ID 2317, SEQ ID 2318, SEQ ID 2319, and SEQ ID
 2320. 27. Theantisense oligonucleotide progranulin agonist according to any one ofclaims 22-26, wherein the antisense oligonucleotide progranulin agonistis selected from the group consisting of SEQ ID 693, SEQ ID 707, SEQ ID708, SEQ ID 709, SEQ ID 710, SEQ ID 711, SEQ ID 720, SEQ ID 721, SEQ ID723, SEQ ID 724, SEQ ID 725, SEQ ID 726, SEQ ID 727, SEQ ID 730, SEQ ID732, SEQ ID 736, SEQ ID 737, SEQ ID 738, SEQ ID 739, SEQ ID 741, SEQ ID743, SEQ ID 745, SEQ ID 747, SEQ ID 758, SEQ ID 759, SEQ ID 760, SEQ ID761, SEQ ID 766, SEQ ID 775, SEQ ID 798, SEQ ID 800, SEQ ID 801, SEQ ID802, SEQ ID 803, SEQ ID 804, SEQ ID 807, SEQ ID 812, SEQ ID 813, SEQ ID814, SEQ ID 816, SEQ ID 818, SEQ ID 819, SEQ ID 822, SEQ ID 823, SEQ ID824, SEQ ID 825, SEQ ID 826, SEQ ID 827, SEQ ID 828, SEQ ID 830, SEQ ID831, SEQ ID 833, SEQ ID 835, SEQ ID 836, SEQ ID 837, SEQ ID 838, SEQ ID839, SEQ ID 840, SEQ ID 841, SEQ ID 842, SEQ ID 843, SEQ ID 844, SEQ ID845, SEQ ID 846, SEQ ID 847, SEQ ID 848, SEQ ID 849, SEQ ID 850, SEQ ID854, SEQ ID 855, SEQ ID 856, SEQ ID 857, SEQ ID 859, SEQ ID 861, SEQ ID866, SEQ ID 867, SEQ ID 868, SEQ ID 869, SEQ ID 871, SEQ ID 873, SEQ ID874, SEQ ID 876, SEQ ID 878, SEQ ID 879, SEQ ID 880, SEQ ID 881, SEQ ID883, SEQ ID 885, SEQ ID 887, SEQ ID 888, SEQ ID 890, SEQ ID 891, SEQ ID892, SEQ ID 893, SEQ ID 895, SEQ ID 897, SEQ ID 906, SEQ ID 909, SEQ ID916, SEQ ID 918, SEQ ID 926, SEQ ID 927, SEQ ID 928, SEQ ID 932, SEQ ID933, SEQ ID 934, SEQ ID 967, SEQ ID 998, SEQ ID 1000, SEQ ID 1001, SEQID 1002, SEQ ID 1003, SEQ ID 1005, SEQ ID 1010, SEQ ID 1011, SEQ ID1012, SEQ ID 1021, SEQ ID 1023, SEQ ID 1024, SEQ ID 1027, SEQ ID 1030,SEQ ID 1037, SEQ ID 1038, SEQ ID 1039, SEQ ID 1041, SEQ ID 1042, SEQ ID1048, SEQ ID 1049, SEQ ID 1050, SEQ ID 1051, SEQ ID 1054, SEQ ID 1058,SEQ ID 1060, SEQ ID 1061, SEQ ID 1063, SEQ ID 1066, SEQ ID 1070, SEQ ID1071, SEQ ID 1072, SEQ ID 1073, SEQ ID 1075, SEQ ID 1078, SEQ ID 1081,SEQ ID 1083, SEQ ID 1084, SEQ ID 1085, SEQ ID 1086, SEQ ID 1091, SEQ ID1092, SEQ ID 1093, SEQ ID 1109, SEQ ID 1111, SEQ ID 1112, SEQ ID 1113,SEQ ID 1114, SEQ ID 1115, SEQ ID 1116, SEQ ID 1117, SEQ ID 1118, SEQ ID1119, SEQ ID 1120, SEQ ID 1121, SEQ ID 1122, SEQ ID 1123, SEQ ID 1124,SEQ ID 1125, SEQ ID 1126, SEQ ID 1127, SEQ ID 1128, SEQ ID 1129, SEQ ID1130, SEQ ID 1132, SEQ ID 1135, SEQ ID 1136, SEQ ID 1137, SEQ ID 1138,SEQ ID 1139, SEQ ID 1140, SEQ ID 1141, SEQ ID 1142, SEQ ID 1143, SEQ ID1144, SEQ ID 1146, SEQ ID 1188, SEQ ID 1189, SEQ ID 1190, SEQ ID 1191,SEQ ID 1192, SEQ ID 1196, SEQ ID 1200, SEQ ID 1201, SEQ ID 1202, SEQ ID1203, SEQ ID 1204, SEQ ID 1205, SEQ ID 1206, SEQ ID 1207, SEQ ID 1208,SEQ ID 1209, SEQ ID 1223, SEQ ID 1224, SEQ ID 1238, SEQ ID 1243, SEQ ID1244, SEQ ID 1258, SEQ ID 1259, SEQ ID 1262, SEQ ID 1263, SEQ ID 1264,SEQ ID 1267, SEQ ID 1268, SEQ ID 1271, SEQ ID 1276, SEQ ID 1282, SEQ ID1283, SEQ ID 1284, SEQ ID 1285, SEQ ID 1286, SEQ ID 1288, SEQ ID 1290,SEQ ID 1291, SEQ ID 1292, SEQ ID 1294, SEQ ID 1297, SEQ ID 1298, SEQ ID1304, SEQ ID 1311, SEQ ID 1313, SEQ ID 1314, SEQ ID 1315, SEQ ID 1344,SEQ ID 1345, SEQ ID 1346, SEQ ID 1347, SEQ ID 1348, SEQ ID 1349, SEQ ID1352, SEQ ID 1355, SEQ ID 1357, SEQ ID 1425, SEQ ID 1426, SEQ ID 1427,SEQ ID 1428, SEQ ID 1430, SEQ ID 1431, SEQ ID 1432, SEQ ID 1433, SEQ ID1434, SEQ ID 1435, SEQ ID 1436, SEQ ID 1437, SEQ ID 1438, SEQ ID 1440,SEQ ID 1441, SEQ ID 1442, SEQ ID 1443, SEQ ID 1444, SEQ ID 1445, SEQ ID1446, SEQ ID 1447, SEQ ID 1448, SEQ ID 1449, SEQ ID 1450, SEQ ID 1451,SEQ ID 1454, SEQ ID 1455, SEQ ID 1456, SEQ ID 1457, SEQ ID 1460, SEQ ID1461, SEQ ID 1462, SEQ ID 1463, SEQ ID 1464, SEQ ID 1467, SEQ ID 1469,SEQ ID 1474, SEQ ID 1478, SEQ ID 1480, SEQ ID 1482, SEQ ID 1488, SEQ ID1492, SEQ ID 1493, SEQ ID 1497, SEQ ID 1498, SEQ ID 1505, SEQ ID 1506,SEQ ID 1507, SEQ ID 1509, SEQ ID 1510, SEQ ID 1512, SEQ ID 1513, SEQ ID1514, SEQ ID 1515, SEQ ID 1517, SEQ ID 1520, SEQ ID 1524, SEQ ID 1525,SEQ ID 1528, SEQ ID 1529, SEQ ID 1530, SEQ ID 1531, SEQ ID 1532, SEQ ID1533, SEQ ID 1534, SEQ ID 1535, SEQ ID 1536, SEQ ID 1537, SEQ ID 1538,SEQ ID 1539, SEQ ID 1540, SEQ ID 1541, SEQ ID 1542, SEQ ID 1544, SEQ ID1545, SEQ ID 1546, SEQ ID 1547, SEQ ID 1548, SEQ ID 1549, SEQ ID 1550,SEQ ID 1551, SEQ ID 1552, SEQ ID 1553, SEQ ID 1554, SEQ ID 1555, SEQ ID1556, SEQ ID 1558, SEQ ID 1560, SEQ ID 1563, SEQ ID 1565, SEQ ID 1568,SEQ ID 1569, SEQ ID 1575, SEQ ID 1577, SEQ ID 1578, SEQ ID 1579, SEQ ID1582, SEQ ID 1583, SEQ ID 1584, SEQ ID 1585, SEQ ID 1586, SEQ ID 1587,SEQ ID 1588, SEQ ID 1589, SEQ ID 1590, SEQ ID 1591, SEQ ID 1593, SEQ ID1594, SEQ ID 1595, SEQ ID 1596, SEQ ID 1599, SEQ ID 1608, SEQ ID 1609,SEQ ID 1610, SEQ ID 1611, SEQ ID 1612, SEQ ID 1613, SEQ ID 1614, SEQ ID1615, SEQ ID 1616, SEQ ID 1617, SEQ ID 1618, SEQ ID 1620, SEQ ID 1621,SEQ ID 1622, SEQ ID 1623, SEQ ID 1624, SEQ ID 1626, SEQ ID 1630, SEQ ID1631, SEQ ID 1633, SEQ ID 1635, SEQ ID 1637, SEQ ID 1638, SEQ ID 1639,SEQ ID 1643, SEQ ID 1644, SEQ ID 1645, SEQ ID 1648, SEQ ID 1649, SEQ ID1651, SEQ ID 1658, SEQ ID 1667, SEQ ID 1669, SEQ ID 1677, SEQ ID 1679,SEQ ID 1681, SEQ ID 1684, SEQ ID 1685, SEQ ID 1686, SEQ ID 1688, SEQ ID1689, SEQ ID 1690, SEQ ID 1692, SEQ ID 1704, SEQ ID 1707, SEQ ID 1708,SEQ ID 1709, SEQ ID 1710, SEQ ID 1711, SEQ ID 1712, SEQ ID 1714, SEQ ID1715, SEQ ID 1717, SEQ ID 1718, SEQ ID 1719, SEQ ID 1720, SEQ ID 1721,SEQ ID 1722, SEQ ID 1723, SEQ ID 1724, SEQ ID 1725, SEQ ID 1726, SEQ ID1727, SEQ ID 1728, SEQ ID 1731, SEQ ID 1732, SEQ ID 1733, SEQ ID 1734,SEQ ID 1735, SEQ ID 1736, SEQ ID 1737, SEQ ID 1738, SEQ ID 1741, SEQ ID1742, SEQ ID 1762, SEQ ID 1764, SEQ ID 1765, SEQ ID 1766, SEQ ID 1767,SEQ ID 1768, SEQ ID 1769, SEQ ID 1770, SEQ ID 1771, SEQ ID 1773, SEQ ID1775, SEQ ID 1776, SEQ ID 1779, SEQ ID 1780, SEQ ID 1781, SEQ ID 1782,SEQ ID 1783, SEQ ID 1784, SEQ ID 1785, SEQ ID 1786, SEQ ID 1787, SEQ ID1789, SEQ ID 1791, SEQ ID 1792, SEQ ID 1794, SEQ ID 1795, SEQ ID 1796,SEQ ID 1800, SEQ ID 1801, SEQ ID 1802, SEQ ID 1804, SEQ ID 1805, SEQ ID1806, SEQ ID 1807, SEQ ID 1808, SEQ ID 1809, SEQ ID 1811, SEQ ID 1812,SEQ ID 1813, SEQ ID 1814, SEQ ID 1815, SEQ ID 1816, SEQ ID 1817, SEQ ID1818, SEQ ID 1819, SEQ ID 1820, SEQ ID 1821, SEQ ID 1822, SEQ ID 1823,SEQ ID 1824, SEQ ID 1832, SEQ ID 1833, SEQ ID 1838, SEQ ID 1839, SEQ ID1840, SEQ ID 1862, SEQ ID 1866, SEQ ID 1868, SEQ ID 1873, SEQ ID 1877,SEQ ID 1883, SEQ ID 1884, SEQ ID 1888, SEQ ID 1889, SEQ ID 1893, SEQ ID1894, SEQ ID 1928, SEQ ID 1929, SEQ ID 1933, SEQ ID 1938, SEQ ID 1939,SEQ ID 1940, SEQ ID 1941, SEQ ID 1943, SEQ ID 1944, SEQ ID 1948, SEQ ID1950, SEQ ID 1952, SEQ ID 1956, SEQ ID 1966, SEQ ID 1985, SEQ ID 1986,SEQ ID 1996, SEQ ID 1997, SEQ ID 1998, SEQ ID 1999, SEQ ID 2000, SEQ ID2005, SEQ ID 2013, SEQ ID 2015, SEQ ID 2020, SEQ ID 2023, SEQ ID 2026,SEQ ID 2028, SEQ ID 2031, SEQ ID 2032, SEQ ID 2033, SEQ ID 2042, SEQ ID2048, SEQ ID 2052, SEQ ID 2053, SEQ ID 2055, SEQ ID 2056, SEQ ID 2057,SEQ ID 2058, SEQ ID 2059, SEQ ID 2060, SEQ ID 2061, SEQ ID 2063, SEQ ID2065, SEQ ID 2066, SEQ ID 2067, SEQ ID 2068, SEQ ID 2070, SEQ ID 2072,SEQ ID 2073, SEQ ID 2075, SEQ ID 2076, SEQ ID 2079, SEQ ID 2080, SEQ ID2081, SEQ ID 2082, SEQ ID 2083, SEQ ID 2084, SEQ ID 2085, SEQ ID 2086,SEQ ID 2087, SEQ ID 2088, SEQ ID 2089, SEQ ID 2090, SEQ ID 2091, SEQ ID2092, SEQ ID 2093, SEQ ID 2094, SEQ ID 2095, SEQ ID 2097, SEQ ID 2116,SEQ ID 2119, SEQ ID 2120, SEQ ID 2121, SEQ ID 2122, SEQ ID 2123, SEQ ID2124, SEQ ID 2125, SEQ ID 2126, SEQ ID 2127, SEQ ID 2146, SEQ ID 2147,SEQ ID 2148, SEQ ID 2158, SEQ ID 2160, SEQ ID 2162, SEQ ID 2163, SEQ ID2165, SEQ ID 2166, SEQ ID 2167, SEQ ID 2168, SEQ ID 2169, SEQ ID 2170,SEQ ID 2171, SEQ ID 2172, SEQ ID 2173, SEQ ID 2174, SEQ ID 2175, SEQ ID2176, SEQ ID 2177, SEQ ID 2181, SEQ ID 2182, SEQ ID 2183, SEQ ID 2184,SEQ ID 2185, SEQ ID 2186, SEQ ID 2187, SEQ ID 2193, SEQ ID 2194, SEQ ID2195, SEQ ID 2196, SEQ ID 2197, SEQ ID 2198, SEQ ID 2199, SEQ ID 2200,SEQ ID 2202, SEQ ID 2203, SEQ ID 2204, SEQ ID 2206, SEQ ID 2208, SEQ ID2209, SEQ ID 2210, SEQ ID 2211, SEQ ID 2212, SEQ ID 2213, SEQ ID 2214,SEQ ID 2216, SEQ ID 2222, SEQ ID 2224, SEQ ID 2239, SEQ ID 2240, SEQ ID2242, SEQ ID 2243, SEQ ID 2244, SEQ ID 2245, SEQ ID 2246, SEQ ID 2247,SEQ ID 2248, SEQ ID 2251, SEQ ID 2252, SEQ ID 2253, SEQ ID 2254, SEQ ID2255, SEQ ID 2256, SEQ ID 2257, SEQ ID 2258, SEQ ID 2259, SEQ ID 2260,SEQ ID 2261, SEQ ID 2262, SEQ ID 2263, SEQ ID 2264, SEQ ID 2265, SEQ ID2266, SEQ ID 2267, SEQ ID 2268, SEQ ID 2269, SEQ ID 2280, SEQ ID 2281,SEQ ID 2282, SEQ ID 2283, SEQ ID 2284, SEQ ID 2285, SEQ ID 2294, SEQ ID2295, SEQ ID 2302, SEQ ID 2307, SEQ ID 2308, SEQ ID 2309, SEQ ID 2310,SEQ ID 2311, SEQ ID 2312, SEQ ID 2316, SEQ ID 2317, SEQ ID 2318, SEQ ID2319, and SEQ ID
 2320. 28. The antisense oligonucleotide progranulinagonist according to any one of claims 1-20, wherein the antisenseoligonucleotide progranulin agonist is or comprises an antisenseoligonucleotide mixmer or totalmer.
 29. The antisense oligonucleotideprogranulin agonist of any one of claims 1-28, wherein the antisenseoligonucleotide progranulin agonist or contiguous nucleotide sequencethereof is 10-20 nucleotides in length.
 30. An antisense oligonucleotideprogranulin agonist having the structure:


31. An antisense oligonucleotide progranulin agonist wherein theoligonucleotide is the oligonucleotide compound TgGccAggGatCagGG (SEQ IDNO: 106) wherein capital letters represent beta-D-oxy LNA nucleosides,lowercase letters represent DNA nucleosides, all LNA C are 5-methylcytosine, and all internucleoside linkages are phosphorothioateinternucleoside linkages.
 32. An antisense oligonucleotide progranulinagonist according to any one of claims 1-31 covalently attached to atleast one conjugate moiety.
 33. An antisense oligonucleotide progranulinagonist according to any one of claims 1-32 wherein the antisenseoligonucleotide progranulin agonist is in the form of a pharmaceuticallyacceptable salt.
 34. An antisense oligonucleotide progranulin agonistaccording to claim 33 wherein the salt is a sodium salt or a potassiumsalt.
 35. A pharmaceutical composition comprising the antisenseoligonucleotide progranulin agonist according to any one of claims 1-34and a pharmaceutically acceptable diluent, solvent, carrier, salt and/oradjuvant.
 36. A pharmaceutical composition according to claim 35,wherein the pharmaceutical composition comprises an aqueous diluent orsolvent, such as phosphate buffered saline.
 37. An in vivo or in vitromethod for enhancing the expression of progranulin in a cell which isexpressing progranulin, said method comprising administering anantisense oligonucleotide progranulin agonist according to any one ofclaims 1-34, or the pharmaceutical composition according to claim 35 orclaim 36 in an effective amount to said cell.
 38. The method accordingto claim 37, wherein the cell is either a human cell or a mammaliancell.
 39. A method for treating or preventing neurological diseasecomprising administering a therapeutically or prophylactically effectiveamount of an antisense oligonucleotide progranulin agonist according toany one of claims 1-34 or the pharmaceutical composition according toclaim 35 or claim 365 to a subject suffering from or susceptible toneurological disease.
 40. The antisense oligonucleotide progranulinagonist according to any one of claims 1-34, or the pharmaceuticalcomposition according to claim 35 or claim 36 for use as a medicament.41. The antisense oligonucleotide progranulin agonist according to anyone of claims 1-33, or the pharmaceutical composition according to claim35 or claim 36 for use in the treatment of a neurological disease. 42.The antisense oligonucleotide progranulin agonist or pharmaceuticalcomposition for use in the treatment of a neurological disease accordingto claim 41, wherein the neurological disease is a TDP-43 pathology. 43.The antisense oligonucleotide progranulin agonist according to any oneof claims 1-34 or the pharmaceutical composition according to claim 35or claim 36 for use in the treatment of progranulin haploinsufficiency.44. Use of the antisense oligonucleotide progranulin agonist accordingto claims 1-34, or the pharmaceutical composition according to claim 35or claim 36 for the preparation of a medicament for treatment orprevention of a neurological disease.
 45. Use of an antisenseoligonucleotide progranulin agonist, or pharmaceutical compositionaccording to claim 44, wherein the neurological disease is a TDP-43pathology.
 46. Use of the antisense oligonucleotide progranulin agonistaccording to claim 1-34, or the pharmaceutical composition according toclaim 35 or claim 36, for the preparation of a medicament for treatmentof progranulin haploinsufficiency.
 47. The method or use according toany one of claims 37-46, wherein the method or use is for the treatmentof fronto temporal dementia (FTD), neuropathologic frontotemporal lobardegeneration or neuroinflammation.